112 results on '"Provoost AP"'
Search Results
2. Tubuloglomerular feedback and prolonged ACE-inhibitor treatment in the hypertensive fawn-hooded rat.
- Author
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Verseput, GH, Braam, B, Provoost, AP, and Koomans, HA
- Abstract
Background: The spontaneously hypertensive fawn-hooded (FHH) rat develops severe glomerulosclerosis with ageing. The afferent arteriolar resistance is low, resulting in a strongly elevated glomerular capillary pressure (PGC). [ABSTRACT FROM PUBLISHER] more...
- Published
- 1998
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3. Editorial comment. Susceptibility genes for end-organ damage. New strategies to understand diabetic and hypertensive nephropathy.
- Author
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Broeckel, U, Shiozawa, M, Kissebah, AH, Provoost, AP, and Jacob, HJ
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- 1998
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4. Different effects of calcium channel blockers on renal damage development in the fawn-hooded hypertensive rat
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Provoost, AP and Van Dokkum, RPE
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- 1999
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5. SORCS1 contributes to the development of renal disease in rats and humans.
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Lazar J, O'Meara CC, Sarkis AB, Prisco SZ, Xu H, Fox CS, Chen MH, Broeckel U, Arnett DK, Moreno C, Provoost AP, and Jacob HJ
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- Animals, Biological Transport genetics, Biological Transport physiology, Female, Genotype, Humans, Hypertension genetics, Hypertension metabolism, Hypertension physiopathology, Kidney Diseases genetics, Kidney Tubules, Proximal metabolism, Kidney Tubules, Proximal physiopathology, Male, Proteinuria genetics, Proteinuria metabolism, Proteinuria physiopathology, Rats, Receptors, Cell Surface genetics, Kidney Diseases metabolism, Kidney Diseases physiopathology, Receptors, Cell Surface metabolism
- Abstract
Many lines of evidence demonstrate that genetic variability contributes to chronic kidney disease susceptibility in humans as well as rodent models. Little progress has been made in discovering causal kidney disease genes in humans mainly due to genetic complexity. Here, we use a minimal congenic mapping strategy in the FHH (fawn hooded hypertensive) rat to identify Sorcs1 as a novel renal disease candidate gene. We investigated the hypothesis that genetic variation in Sorcs1 influences renal disease susceptibility in both rat and human. Sorcs1 is expressed in the kidney, and knocking out this gene in a rat strain with a sensitized genome background produced increased proteinuria. In vitro knockdown of Sorcs1 in proximal tubule cells impaired protein trafficking, suggesting a mechanism for the observed proteinuria in the FHH rat. Since Sorcs1 influences renal function in the rat, we went on to test this gene in humans. We identified associations between single nucleotide polymorphisms in SORCS1 and renal function in large cohorts of European and African ancestry. The experimental data from the rat combined with association results from different ethnic groups indicates a role for SORCS1 in maintaining proper renal function. more...
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- 2013
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6. Renal vascular dysfunction precedes the development of renal damage in the hypertensive Fawn-Hooded rat.
- Author
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Ochodnický P, Henning RH, Buikema HJ, de Zeeuw D, Provoost AP, and van Dokkum RP
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- Age Factors, Aging, Animals, Aorta, Thoracic physiopathology, Biological Factors metabolism, Blood Pressure, Cyclooxygenase 1 metabolism, Disease Models, Animal, Disease Progression, Dose-Response Relationship, Drug, Endothelium, Vascular metabolism, Endothelium, Vascular physiopathology, Hypertension complications, Hypertension metabolism, Hypertension pathology, Kidney pathology, Kidney Diseases metabolism, Kidney Diseases pathology, Kidney Diseases physiopathology, Male, Membrane Proteins metabolism, Nitric Oxide metabolism, Prostaglandins metabolism, Proteinuria etiology, Proteinuria pathology, Proteinuria physiopathology, Rats, Rats, Inbred Strains, Renal Artery drug effects, Renal Artery metabolism, Vasoconstrictor Agents pharmacology, Vasodilator Agents pharmacology, Hypertension physiopathology, Kidney blood supply, Kidney Diseases etiology, Renal Artery physiopathology, Renal Circulation drug effects, Vasoconstriction drug effects, Vasodilation drug effects
- Abstract
It is unknown whether generalized vascular dysfunction precedes the development of kidney disease. Therefore, we studied myogenic constriction and endothelium-mediated dilatory responses in two inbred Fawn-Hooded (FH) rat strains, one of which spontaneously develops hypertension, proteinuria, and glomerulosclerosis (FHH), whereas the other (FHL) does not. Small renal, mesenteric resistance arteries and thoracic aorta isolated from FH rats before (7 wk old) and after the development of mild proteinuria (12 wks old) were mounted in perfused and isometric set-ups, respectively. Myogenic response, endothelium-dependent relaxation, and the contribution of endothelium-mediated dilatory compounds were studied using their respective inhibitors. Myogenic reactivity was assessed constructing pressure-diameter curves in the presence and absence of calcium. At the age of 7 wk, renal arteries isolated from kidneys of FHH rats developed significantly lower myogenic tone compared with FHL, most likely because of excessive cyclo-oxygenase 1-mediated production of constrictive prostaglandins. Consequently, young FHH demonstrated reduced maximal myogenic tone (22 +/- 4.8 vs. 10.8 +/- 2.0%, P = 0.03) and the peak myogenic index (-6.9 +/- 4.8 vs. 0.6 +/- 0.8%/mmHg, P = 0.07 for FHL vs. FHH, respectively). Active myogenic curves obtained in mesenteric arteries isolated from 7-wk-old rats did not differ between either strain, demonstrating a similar level of systemic myogenic tone in FHL and FHH rats. Therefore, before any renal end-organ damage is present, myogenic response seems selectively impaired in renal vasculature of FHH rats. Aortic reactivity did not differ between FHL and FHH at the time points studied. The present study shows that vascular dysfunction in both small renal and systemic arteries precedes renal end-organ damage in a spontaneous model of hypertension-associated renal damage. These early vascular changes might be potentially involved in the increased susceptibility of FHH rats to renal injury. more...
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- 2010
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7. Does angiotensin receptor recycling regulate blood pressure?
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Provoost AP
- Subjects
- Animals, Models, Biological, Blood Pressure physiology, Receptors, Angiotensin metabolism
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- 2006
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8. Identification of a QTL on chromosome 1 for impaired autoregulation of RBF in fawn-hooded hypertensive rats.
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López B, Ryan RP, Moreno C, Sarkis A, Lazar J, Provoost AP, Jacob HJ, and Roman RJ
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- Animals, Genetic Linkage, Homeostasis, Hypertension physiopathology, Proteinuria physiopathology, Rats, Regional Blood Flow, Chromosome Mapping, Hypertension genetics, Kidney blood supply, Quantitative Trait Loci
- Abstract
The present study evaluated whether the impairment in autoregulation of renal blood flow (RBF) in the fawn-hooded Hypertensive (FHH) rat colocalizes with the Rf-1 region on chromosome 1 that has been previously linked to the development of proteinuria in this strain. Autoregulation of RBF was measured in FHH and a consomic strain (FHH.1(BN)) in which chromosome 1 from the Brown-Norway (BN) rat was introgressed into the FHH genetic background. The autoregulation indexes (AI) averaged 0.80 +/- 0.08 in the FHH and 0.19 +/- 0.05 in the FHH.1(BN) rats. We next performed a genetic linkage analysis for autoregulation of RBF in 85 F2 rats generated from a backcross of FHH.1(BN) consomic and FHH rats. The results revealed a significant quantitative trait locus (QTL) with a peak logarithm of the odds score of 6.3 near marker D1Rat376. To confirm the existence of this QTL, five overlapping congenic strains were created that spanned the region from markers D1Rat234 to D1Mit14. Transfer of a region of BN chromosome 1 from markers D1Mgh13 to D1Rat89 into the FHH genetic background improved autoregulation of RBF (AI = 0.23 +/- 0.04) and reduced protein excretion. In contrast, RBF was poorly autoregulated and the rats were not protected from proteinuria in congenic strains in which other regions of chromosome 1 that exclude the D1Rat376 marker were transferred. These results indicate that there is a gene(s) that influences autoregulation of RBF and proteinuria between markers D1Mgh13 and D1Rat89 on chromosome 1 that lies within the confidence interval of the Rf-1 QTL previously linked to the development of proteinuria in FHH rats. more...
- Published
- 2006
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9. Synergistic QTL interactions between Rf-1 and Rf-3 increase renal damage susceptibility in double congenic rats.
- Author
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Van Dijk SJ, Specht PA, Lazar J, Jacob HJ, and Provoost AP
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- Administration, Oral, Animals, Animals, Congenic, Blood Pressure genetics, Chromosome Mapping, Chromosomes, Mammalian, Enzyme Inhibitors administration & dosage, Follow-Up Studies, Genetic Markers, Genome, Homozygote, Hypertension, Renal etiology, Kidney Diseases physiopathology, Male, NG-Nitroarginine Methyl Ester administration & dosage, Nephrectomy, Proteinuria genetics, Rats, Rats, Inbred ACI, Renal Circulation genetics, Survival Analysis, Time Factors, Genetic Predisposition to Disease, Homeostasis genetics, Hypertension, Renal genetics, Kidney Diseases genetics, Quantitative Trait Loci
- Abstract
The FHH (fawn-hooded hypertensive) rat is a model of hypertension-associated chronic kidney damage. Five interacting quantitative trait loci (QTLs), named Rf-1-Rf-5, determine the high renal susceptibility. The aim of the present study was to investigate a possible interaction between Rf-1 and Rf-3. Differences in renal susceptibility between ACI (August x Copenhagen Irish) controls, Rf-1A and Rf-3 single congenics, and Rf-1A+3 double congenic rats were assessed using four different treatments: two-kidney control (2K), 2K plus N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension (2K+L-NAME), unilateral nephrectomy (UNX), and UNX plus L-NAME-induced hypertension (UNX+L-NAME). Proteinuria (UPV) and systolic blood pressure (SBP) were assessed after 6, 12, and 18 weeks, while the incidence of glomerulosclerosis (%FGS) was determined at the end of the experiment. In a separate experiment, renal autoregulation was assessed in 13-15-week old 2K rats of all four strains. Compared to ACI rats, small increases in renal susceptibility were found in Rf-1A and Rf-3 single congenics following 2K+L-NAME, UNX, and UNX+L-NAME treatments. However, in the Rf-1A+3 double congenics, a major increase in renal susceptibility was found with all four treatments. Both Rf-1A and Rf-1A+3 congenic rats had an impaired renal autoregulation. In contrast, the Rf-3 had a normal autoregulation, similar to that of the ACI rat. These findings indicate that Rf-1 and Rf-3 alone slightly increase the susceptibility to the development of renal damage. However, a synergistic interaction between these two QTLs markedly enhances renal susceptibility. In contrast to the Rf-1 region, the Rf-3 region does not carry genes influencing renal autoregulation. more...
- Published
- 2006
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10. Absence of an interaction between the Rf-1 and Rf-5 QTLs influencing susceptibility to renal damage in rats.
- Author
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van Dijk SJ, Specht PA, Lazar J, Jacob HJ, and Provoost AP
- Subjects
- Albuminuria etiology, Animals, Animals, Congenic, Blood Pressure, Enzyme Inhibitors, Glomerulosclerosis, Focal Segmental etiology, Homeostasis, Hypertension chemically induced, Hypertension physiopathology, NG-Nitroarginine Methyl Ester, Nephrectomy, Rats, Rats, Inbred Strains, Renal Circulation, Renal Insufficiency etiology, Renal Insufficiency physiopathology, Survival Analysis, Epistasis, Genetic, Genetic Predisposition to Disease, Hypertension genetics, Quantitative Trait Loci, Renal Insufficiency complications, Renal Insufficiency genetics
- Abstract
Background: Previous studies showed that combining the Rf-1 and Rf-3 or Rf-4 QTLs of FHH induced synergistic interactions markedly enhancing renal susceptibility. The present study aimed to determine the presence of such interaction between the Rf-1 and Rf-5 QTLs., Methods: Renal damage susceptibility was assessed in Rf-1B, Rf-1B+5, Rf-1B+4 congenics and ACI control rats in four situations: two-kidney control (2K), unilateral nephrectomy (UNX), L-NAME-induced hypertension (2K+L-NAME) and UNX+L-NAME. Albuminuria (UAV) and systolic blood pressure (SBP) were measured during 18 weeks of follow-up. In separate experiments, renal autoregulation was assessed in 2K rats., Results: In all four situations, Rf-1B+4 rats developed more severe UAV than ACI, Rf-1B and Rf-1B+5. There were no significant differences in UAV between Rf-1B and Rf-1B+5 rats. In the 2K and UNX situation no differences in SBP were noted between all four strains. With 2K+L-NAME and UNX+L-NAME treatment, SBP in double congenics was higher than that of ACI and Rf-1B rats. Renal autoregulation was similarly impaired in all three congenic strains., Conclusion: We conclude that the Rf-5 region, alone or in the presence of Rf-1B, does not affect the development of renal damage. We cannot substantiate that the Rf-5 region contains genes influencing renal damage susceptibility., (Copyright 2006 S. Karger AG, Basel.) more...
- Published
- 2006
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11. Interaction between Rf-1 and Rf-4 quantitative trait loci increases susceptibility to renal damage in double congenic rats.
- Author
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Van Dijk SJ, Specht PA, Lutz MM, Lazar J, Jacob HJ, and Provoost AP
- Subjects
- Albuminuria mortality, Animals, Animals, Congenic, Blood Pressure genetics, Chromosomes, Mammalian, Genetic Linkage, Genetic Predisposition to Disease genetics, Homeostasis genetics, Homozygote, Hypertension, Renal mortality, Rats, Rats, Inbred ACI, Renal Circulation genetics, Specific Pathogen-Free Organisms, Survival Rate, Albuminuria genetics, Albuminuria physiopathology, Hypertension, Renal genetics, Hypertension, Renal physiopathology, Quantitative Trait Loci
- Abstract
Background: Five quantitative trait loci (QTLs), Rf-1 to Rf-5, were found in Fawn-Hooded hypertensive (FHH) rats influencing susceptibility to renal damage. Previously, we found that single transfer of the Rf-1 QTL from FHH rats onto the renal-resistant August x Copenhagen Irish (ACI) strain caused a small increase in renal susceptibility. To investigate the separate role of the Rf-4 QTL and its interaction with Rf-1, we generated a single congenic strain carrying Rf-4 and a double congenic carrying both Rf-1 and Rf-4., Methods: Differences in renal susceptibility between ACI, Rf-1A, and Rf-4 single congenics and Rf-1A+4 double congenics were assessed using four different treatments: control (two-kidney), two-kidney with l-arginine analogue N-nitro-l-arginine methyl ester (L-NAME)-induced hypertension, unilateral nephrectomy, and unilateral nephrectomy + L-NAME. In separate experiments, renal blood flow (RBF) autoregulation was compared between two-kidney ACI and congenic rats., Results: Compared to ACI, Rf-1A rats developed more renal damage, while Rf-4 rats did not. The most severe renal damage was found in the Rf-1A+4 double congenic rats. Analysis of variance (ANOVA) demonstrated a significant interaction between the Rf-1A and Rf-4 QTLs. The magnitude of the interaction varied with the type and duration of the treatment. The RBF autoregulation was impaired in Rf-1A single and Rf-1A+4 double congenics, while in Rf-4 single congenics it was similar to that of ACI controls., Conclusion: These findings indicate that the Rf-1 QTL directly influences renal susceptibility and autoregulation. In contrast, the Rf-4 QTL shows no direct effects, but significantly increases susceptibility to renal damage via an interaction with Rf-1. more...
- Published
- 2005
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12. RF-2 gene modulates proteinuria and albuminuria independently of changes in glomerular permeability in the fawn-hooded hypertensive rat.
- Author
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Rangel-Filho A, Sharma M, Datta YH, Moreno C, Roman RJ, Iwamoto Y, Provoost AP, Lazar J, and Jacob HJ
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- Animals, Animals, Congenic, Conserved Sequence, Genomics, Humans, Hypertension genetics, Hypertension metabolism, Permeability, Rats, Rats, Inbred BN, Rats, Inbred Strains, rab GTP-Binding Proteins metabolism, Albuminuria genetics, Hypertension physiopathology, Kidney Glomerulus metabolism, Proteinuria genetics, rab GTP-Binding Proteins genetics
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- 2005
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13. Renal damage susceptibility and autoregulation in RF-1 and RF-5 congenic rats.
- Author
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Van Dijk SJ, Specht PA, Lazar J, Jacob HJ, and Provoost AP
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- Albuminuria genetics, Animals, Blood Pressure genetics, Chimera, Enzyme Inhibitors, Glomerulosclerosis, Focal Segmental genetics, Hypertension etiology, Kidney Diseases physiopathology, Male, NG-Nitroarginine Methyl Ester, Nephrectomy, Proteinuria genetics, Rats, Rats, Inbred ACI, Rats, Inbred Strains, Animals, Congenic genetics, Genetic Predisposition to Disease, Homeostasis genetics, Hypertension genetics, Kidney Diseases genetics, Quantitative Trait Loci, Renal Circulation genetics
- Abstract
Background: Linkage analyses of crosses of rats susceptible to renal damage, fawn-hooded hypertensive (FHH), and those resistant to kidney damage, August x Copenhagen Irish (ACI), indicated that five quantitative trait loci (QTLs), Rf-1 to Rf-5, influence proteinuria (UPV), albuminuria (UAV) and focal glomerulosclerosis (FGS). Here we present data obtained in congenic rats to directly assess the role of the Rf-1 and Rf-5 QTLs., Methods: Renal damage (UPV, UAV, and FGS) was assessed in ACI, ACI.FHH-(D1Rat324-D1Rat156)(Rf-1B), and ACI.FHH-(D17Rat117-D17Arb5)(D17Rat180-D17Rat51) (Rf-5) congenic rats in the two-kidney (2K) control situation, and following L-NAME-induced hypertension, unilateral nephrectomy (UNX), and UNX combined with L-NAME. In addition we investigated renal blood flow (RBF) autoregulation in 2K congenic and parental ACI and FHH rats., Results: Compared to ACI, Rf-1B congenic rats showed a significant increase in susceptibility to renal damage after all three treatments. The increase was most pronounced after UNX with L-NAME. In contrast, the degree of renal damage in Rf-5 congenic rats was not different from the ACI. Like FHH, Rf-1B rats had impaired renal autoregulation. In contrast, RBF autoregulation of Rf-5 rats does not differ from ACI., Conclusion: The Rf-5 QTL does not show any direct effect. The Rf-1 QTL carries one or more genes impairing renal autoregulation and influencing renal damage susceptibility. Whether these are the same genes remains to be established., (Copyright 2005 S. Karger AG, Basel.) more...
- Published
- 2005
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14. Genetic mapping and characterization of the bleeding disorder in the fawn-hooded hypertensive rat.
- Author
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Datta YH, Wu FC, Dumas PC, Rangel-Filho A, Datta MW, Ning G, Cooley BC, Majewski RR, Provoost AP, and Jacob HJ
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- Animals, Blood Coagulation Disorders pathology, Blood Platelets pathology, Blood Platelets ultrastructure, Chromosomes, Clinical Enzyme Tests, Disease Models, Animal, Genotype, Hermanski-Pudlak Syndrome blood, Hypertension, Platelet Function Tests, Platelet Storage Pool Deficiency pathology, Rats, Rats, Inbred Strains, Retina pathology, Blood Coagulation Disorders genetics, Chromosome Mapping, Platelet Storage Pool Deficiency genetics
- Abstract
Release of platelet dense granule contents occurs in response to vascular injury, playing an important role in platelet aggregation and primary hemostasis. Abnormalities of the platelet dense granules results in a bleeding disorder of variable severity termed "storage pool defect" (SPD). We have examined the fawn-hooded hypertensive (FHH) rat as a model of SPD in order to genetically map the locus (Bd) responsible for prolonged bleeding. Platelet function assays of the FHH rat confirmed the presence of a platelet dense granule SPD. However electron microscopy and lysosomal enzyme assays indicated differences between the FHH rat and other rodent models of SPD. Genetic mapping through the use of congenic FHH rats localized the Bd locus to an approximately 1 cM region on rat chromosome 1. Through the use of comparative mapping between species and analysis of the initial draft of the rat genome assembly, six known and thirty-four putative genes were identified in the Bd locus. None of these genes have been previously implicated in platelet function. Therefore positional cloning of the gene responsible for the bleeding disorder in the FHH rat will lead to new insights in platelet physiology, with implications for diagnosis and management of hemostatic and thrombotic disorders. more...
- Published
- 2003
15. Transfer of the Rf-1 region from FHH onto the ACI background increases susceptibility to renal impairment.
- Author
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Provoost AP, Shiozawa M, Van Dokkum RP, and Jacob HJ
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- Animals, Animals, Congenic, Blood Pressure genetics, Crosses, Genetic, Female, Gene Transfer Techniques, Genetic Markers genetics, Kidney Failure, Chronic physiopathology, Kidney Function Tests, Kidney Glomerulus physiopathology, Male, Rats, Rats, Inbred ACI, Systole genetics, Transgenes genetics, Genetic Predisposition to Disease genetics, Kidney Failure, Chronic genetics
- Abstract
The genetically hypertensive fawn-hooded (FHH/Eur) rat is characterized by the early presence of systolic and glomerular hypertension, progressive proteinuria (UPV), and albuminuria (UAV), and focal glomerulosclerosis, resulting in premature death from renal failure. Previous studies showed that at least five genetic loci (Rf-1 to Rf-5) were linked to the development of renal impairment. Of these five, Rf-1 appears to play a major role. To study the impact of Rf-1 in the absence of the other loci, we transferred the Rf-1 region of chromosome 1, between the markers D1Mit34 and D1Rat156, Rf-1B for short, onto the genomic background of the normotensive August x Copenhagen Irish (ACI) rat. In this congenic strain, named ACI.FHH-D1Mit34/Rat156 or ACI.FHH-Rf1B, we challenged the renal hemodynamic function of these animals by studying the effects of unilateral nephrectomy (UNX) alone, or combined with N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Following UNX, the congenic strain developed significantly more UPV and UAV than the ACI progenitor. The differences were even more pronounced when UNX was combined with an L-NAME-induced rise in systolic blood pressure to about 150 mmHg, i.e., the level of hypertension present in the parental FHH strain. These findings indicate that the Rf-1B region of the FHH rat contains at least one gene affecting the susceptibility to progressive renal failure, especially in the presence of an increase in blood pressure. more...
- Published
- 2002
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16. Reduced reactivity of renal microvessels to pressure and angiotensin II in fawn-hooded rats.
- Author
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van Rodijnen WF, van Lambalgen TA, Tangelder GJ, van Dokkum RP, Provoost AP, and ter Wee PM
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- Animals, Arterioles drug effects, Arterioles physiology, Blood Pressure physiology, Hydronephrosis physiopathology, Male, Perfusion, Rats, Rats, Sprague-Dawley, Rats, Wistar, Renal Artery drug effects, Renal Artery physiology, Angiotensin II pharmacology, Hypertension physiopathology, Kidney blood supply, Renal Circulation drug effects, Renal Circulation physiology
- Abstract
Fawn-Hooded rats possess an increased risk to develop glomerular damage. Both an impaired control of preglomerular resistance and an elevated postglomerular resistance have been implicated. In the present study, we directly assessed the myogenic reactivity of distal interlobular arteries and afferent arterioles from hypertensive and normotensive Fawn-Hooded rats compared with Sprague-Dawley and Wistar rats, which are known to be resistant for developing renal disease. Pressure-response curves were made in isolated perfused hydronephrotic kidneys from these rats. In addition, increasing concentrations of angiotensin II were added to the perfusate to determine the reactivity of interlobular arteries, afferent arterioles, and efferent arterioles to this peptide. Preglomerular vessels from hypertensive and normotensive Fawn-Hooded rats exhibited an impaired reactivity to both pressure and angiotensin II compared with that of Sprague-Dawley and Wistar rats. Basal efferent arteriolar diameters were similar among the 4 strains of rat. In addition, efferent arterioles from hypertensive and normotensive Fawn-Hooded rats displayed a reduced sensitivity to angiotensin II. Our observations demonstrate that in Fawn-Hooded rats, 2 components of preglomerular resistance control are impaired: the myogenic and the angiotensin II response. In addition, efferent arteriolar reactivity to angiotensin II is not elevated but lowered in these rats. Therefore, a deficit in preglomerular resistance control is the most important intrinsic factor involved in the increased susceptibility of Fawn-hooded rats to develop renal disease. more...
- Published
- 2002
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17. Upregulation of juxtaglomerular NOS1 and COX-2 precedes glomerulosclerosis in fawn-hooded hypertensive rats.
- Author
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Weichert W, Paliege A, Provoost AP, and Bachmann S
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- Animals, Cyclooxygenase 2, Gene Expression Regulation, Enzymologic, Glomerulosclerosis, Focal Segmental pathology, Hypertension pathology, Isoenzymes metabolism, Juxtaglomerular Apparatus pathology, Loop of Henle enzymology, Loop of Henle pathology, Male, Nitric Oxide, Nitric Oxide Synthase metabolism, Nitric Oxide Synthase Type I, Prostaglandin-Endoperoxide Synthases metabolism, Prostaglandins metabolism, RNA, Messenger analysis, Rats, Rats, Inbred Strains, Renin metabolism, Glomerulosclerosis, Focal Segmental metabolism, Hypertension metabolism, Isoenzymes genetics, Juxtaglomerular Apparatus enzymology, Nitric Oxide Synthase genetics, Prostaglandin-Endoperoxide Synthases genetics
- Abstract
This study describes elevated histochemical signals for nitric oxide synthase-1 (NOS1) and cyclooxygenase-2 (COX-2) in juxtaglomerular apparatus (JGA) and adjacent thick ascending limb of the kidney of fawn-hooded hypertensive rats (FHH). Two different age groups of FHH (8 and 16 wk; FHH8 and FHH16, respectively) were compared with genetically related fawn-hooded rats with normal blood pressure (FHL) that served as controls. Histopathological changes in FHH comprised focal segmental glomerulosclerosis (FSGS), focal matrix overexpression, and a moderate arteriolopathy with hypertrophy of the media, enhanced immunoreactivity for alpha-smooth muscle actin, and altered distribution of myofibrils. Macula densa NOS activity, as expressed by NADPH-diaphorase staining, and NOS1 mRNA abundance were significantly elevated in FHH8 (+153 and +88%; P < 0.05) and FHH16 (+93 and +98%; P < 0.05), respectively. Even higher elevations were registered for COX-2 immunoreactivity in FHH8 (+166%; P < 0.05) and FHH16 (+157%; P < 0.05). The intensity of renin immunoreactivity and renin mRNA expression in afferent arterioles was also elevated in FHH8 (+51 and +166%; P < 0.05) and FHH16 (+105 and +136%; P < 0.05), respectively. Thus we show that coordinate upregulation of tubular NOS1, COX-2, and renin expression precedes, and continues after, the manifestation of glomerulosclerotic damage in FHH. These observations may have implications in understanding the role of local paracrine mediators in glomerular disease. more...
- Published
- 2001
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18. Tracer studies in the rat demonstrate misdirected filtration and peritubular filtrate spreading in nephrons with segmental glomerulosclerosis.
- Author
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Kriz W, Hartmann I, Hosser H, Hähnel B, Kränzlin B, Provoost AP, and Gretz N
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- Animals, Ferritins pharmacokinetics, Ferrocyanides pharmacokinetics, Glomerulosclerosis, Focal Segmental complications, Glomerulosclerosis, Focal Segmental genetics, Glomerulosclerosis, Focal Segmental metabolism, Hypertension complications, Hypertension genetics, Lissamine Green Dyes pharmacokinetics, Microscopy, Electron, Nephrons metabolism, Nephrons pathology, Rats, Rats, Mutant Strains, Rats, Wistar, Tissue Distribution, Glomerulosclerosis, Focal Segmental pathology
- Abstract
In two genetic models of "classic" focal segmental glomerulosclerosis (FSGS), the Milan normotensive and the Fawn-hooded hypertensive rats, tracer studies were performed to test the hypothesis that misdirected glomerular filtration and peritubular filtrate spreading are relevant mechanisms that contribute to nephron degeneration in this disease. Two exogenous tracers, lissamine green and horse spleen ferritin, were administered by intravenous injection and subsequently traced histologically in serial kidney sections. In contrast to control rats, both tracers in kidneys of Milan normotensive and Fawn-hooded hypertensive rats with established FSGS were found to accumulate extracellularly at the following sites: (1) within tuft adhesions to Bowman's capsule and associated paraglomerular spaces, (2) at the glomerulotubular junction contained within extensions of the paraglomerular spaces onto the tubule, and (3) within subepithelial peritubular spaces eventually encircling the entire proximal convolution of an affected nephron. This distribution strongly suggests the existence of misdirected filtration into tuft adhesions to Bowman's capsule and subsequent spreading of the filtrate around the entire circumference of a glomerulus and, alongside the glomerulotubular junction, onto the outer aspect of the corresponding tubule. This leads to an interstitial response that consists of the formation of a barrier of sheet-like fibroblast processes around the affected nephron, which confines the filtrate spreading and, subsequently, the destructive process to the affected nephron. No evidence was found that either misdirected filtration and peritubular filtrate spreading themselves or the associated tubulo-interstitial process led to the transfer of the injury from an affected nephron to an unaffected nephron. It is concluded that in the context of FSGS development, misdirected filtration and peritubular filtrate spreading are important damaging mechanisms that underlie the extension of glomerular injury to the corresponding tubulointerstitium, thus leading finally to degeneration of both the glomerulus and the tubule of a severely injured nephron. more...
- Published
- 2001
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19. Evidence of gene-gene interactions in the genetic susceptibility to renal impairment after unilateral nephrectomy.
- Author
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Shiozawa M, Provoost AP, Dokkum RPEV, Majewski RR, and Jacob HJ
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- Animals, Chromosome Mapping, Humans, Quantitative Trait, Heritable, Rats, Rats, Inbred ACI, Rats, Inbred Strains, Sequence Homology, Species Specificity, Genetic Predisposition to Disease genetics, Kidney Diseases etiology, Kidney Diseases genetics, Nephrectomy adverse effects
- Abstract
The number of patients with hypertension-associated end-stage renal failure (ESRF) continues to increase despite improved antihypertensive management and early detection programs. Variation for the development of renal complications in hypertension may reflect independent genetic susceptibility to ESRF. The genetically hypertensive fawn-hooded rat is characterized by the early presence of systolic hypertension, glomerular hypertension, progressive proteinuria (UPV), and focal glomerulosclerosis (FGS), resulting in premature death as a result of renal failure. In the present study, the genetic basis of hypertension-associated ESRF in an F2 intercross consisting of 337 animals, in which systolic BP, UPV, albuminuria, and FGS, were studied at 8 wk after a unilateral nephrectomy performed at 5 to 6 wk of age. A total genome scan, consisting of 418 markers, was used to identify regions that contribute to the pathogenesis of UPV and FGS. Linkage analysis revealed five loci involved in the development of renal impairment. Of these five, two (Rf-1, Rf-2) had been identified previously. There seems to be strong interactive effects between the various loci and their impact on UPV and the other parameters of renal impairment, as well as an interaction with BP. In particular, Rf-1 seems to play a major role in determining the severity of the disease. This study is the first to report the interaction of more than two loci to produce progressive renal failure, suggesting that the genetic dissection of renal failure in humans will require understanding of how multiple genes interact with each other and BP to produce ESRF. more...
- Published
- 2000
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20. Blood pressure and the susceptibility to renal damage after unilateral nephrectomy and L-NAME-induced hypertension in rats.
- Author
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van Dokkum RP, Jacob HJ, and Provoost AP
- Subjects
- Albuminuria etiology, Animals, Enzyme Inhibitors, Glomerular Filtration Rate, Glomerulosclerosis, Focal Segmental pathology, Hypertension chemically induced, Hypertension urine, In Vitro Techniques, Kidney pathology, Kidney physiopathology, NG-Nitroarginine Methyl Ester, Postoperative Period, Rats, Rats, Inbred Strains genetics, Regression Analysis, Systole, Blood Pressure, Genetic Predisposition to Disease, Glomerulosclerosis, Focal Segmental genetics, Hypertension genetics, Hypertension physiopathology, Nephrectomy methods
- Abstract
Background: Fawn-hooded hypertensive (FHH) rats carry several genes which determine the susceptibility to develop renal damage, while renal damage resistant August x Copenhagen Irish (ACI) rats do not. Kidneys from heterozygous (FHH x ACI) F(1) rats, appear to be largely, but not completely, protected after blood pressure elevation with N(omega)-nitro-L-arginine methyl ester (L-NAME). We examined the role of an increased haemodynamic burden on the development of renal damage combining unilateral nephrectomy (UNx)- and L-NAME-induced hypertension in F(1) and ACI rats. Additionally, we investigated whether a general toxic effect of L-NAME, independent from a blood pressure elevation, caused renal damage in F(1) rats in animals simultaneously treated with L-NAME and the ACE inhibitor lisinopril., Methods: Surgery was performed and L-NAME treatment (50 or 150 mg/l) was started at the age of 15 weeks. Systolic blood pressure (SBP) and urinary albumin excretion (UaV) were measured at 6 and 12 weeks post-UNx, followed by autopsy to determine the incidence of focal glomerulosclerosis (FGS). Using lisinopril (LIS) and L-NAME, another group of rats was evaluated at 12, 18, and 24 weeks after start of treatment., Results: At similar L-NAME intake, F, rats developed more severe hypertension and more UaV than ACI rats. The increase in UaV per mmHg increase in SBP was fivefold higher in F(1) compared with ACI rats. In F(1) rats, the increase in UaV per percentage incidence increase in FGS was three times higher. In LIS treated F(1) rats, no significant UaV or FGS was measured at low blood pressure levels, indicating that renal damage in hypertensive F(1) rats is not a direct effect of L-NAME, but the result of the high blood pressure or another action of the renin-angiotensin system., Conclusion: We conclude that heterozygosity for the genes influencing the development of renal damage in the FHH strain increases the susceptibility of the kidney to develop damage after UNx combined with systemic hypertension. more...
- Published
- 2000
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21. New target regions for human hypertension via comparative genomics.
- Author
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Stoll M, Kwitek-Black AE, Cowley AW Jr, Harris EL, Harrap SB, Krieger JE, Printz MP, Provoost AP, Sassard J, and Jacob HJ
- Subjects
- Animals, Humans, Likelihood Functions, Linkage Disequilibrium genetics, Mice, Predictive Value of Tests, Quantitative Trait, Heritable, Rats, Rats, Inbred ACI, Rats, Inbred BN, Rats, Inbred Dahl, Rats, Inbred SHR, Rats, Inbred WKY, Genome, Human, Hypertension genetics
- Abstract
Models of human disease have long been used to understand the basic pathophysiology of disease and to facilitate the discovery of new therapeutics. However, as long as models have been used there have been debates about the utility of these models and their ability to mimic clinical disease at the phenotypic level. The application of genetic studies to both humans and model systems allows for a new paradigm, whereby a novel comparative genomics strategy combined with phenotypic correlates can be used to bridge between clinical relevance and model utility. This study presents a comparative genomic map for "candidate hypertension loci in humans" based on translating QTLs between rat and human, predicting 26 chromosomal regions in the human genome that are very likely to harbor hypertension genes. The predictive power appears robust, as several of these regions have also been implicated in mouse, suggesting that these regions represent primary targets for the development of SNPs for linkage disequilibrium testing in humans and/or provide a means to select specific models for additional functional studies and the development of new therapeutics. more...
- Published
- 2000
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22. ACE inhibition delays development of terminal renal failure in the presence of severe albuminuria.
- Author
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Verseput GH, Koomans HA, Braam B, Weening JJ, and Provoost AP
- Subjects
- Albuminuria complications, Albuminuria mortality, Albuminuria physiopathology, Animals, Glomerular Filtration Rate, Hemodynamics, Kidney Failure, Chronic complications, Kidney Failure, Chronic mortality, Kidney Failure, Chronic physiopathology, Male, Rats, Severity of Illness Index, Survival Rate, Time Factors, Albuminuria drug therapy, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Kidney Failure, Chronic drug therapy
- Abstract
The hypertensive fawn-hooded (FHH) rat develops progressive albuminuria (UalbV) and focal glomerulosclerosis (FGS). Early-onset angiotensin-converting enzyme inhibition (ACE-i) completely prevented the development of hypertension, UalbV, and FGS. ACE-i was still effective when the start of treatment was delayed, albeit less than early-onset treatment. In this study, we examined whether more advanced renal damage reduces the efficacy of ACE-i, and, if so, which factors dampen the efficacy. ACE-i was started in 36-week-old FHH rats, and follow-up consisted of regular assessment of systolic blood pressure (SBP) and UalbV. Untreated rats, matched for age, SBP, and UalbV, served as controls. In separate groups, untreated or treated with ACE-i from either week 7 or week 36, glomerular hemodynamics and FGS were determined at week 40. ACE-i normalized SBP and markedly reduced UalbV. The Initial UalbV response to ACE-i was inversely correlated with pretreatment UalbV, but despite control of SBP, UalbV rose again. Eventually, rats died of terminal renal failure. Life expectancy was significantly increased in treated rats. In both untreated and treated rats, there was a significant inverse correlation between baseline UalbV and survival time. However, the gain in survival time decreased when pretreatment UalbV was higher. Late-onset ACE-i reduced glomerular capillary pressure to the same extent as early-onset ACE-i. There was a significant linear correlation between FGS and UalbV. We conclude that in FHH rats with advanced renal damage, ACE-i slows down the progression to terminal renal failure. The outcome is an increased survival time that is inversely correlated with baseline UalbV. more...
- Published
- 2000
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23. Directing portal flow is essential for graft survival in auxiliary partial heterotopic liver transplantation in the dog.
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de Jonge J, Madern GC, Terpstra OT, Sinaasappel M, Molenaar JC, Provoost AP, and Tilanus HW
- Subjects
- Animals, Dogs, Liver Transplantation diagnostic imaging, Liver Transplantation physiology, Metabolism, Inborn Errors surgery, Portal System surgery, Radionuclide Imaging, Radiopharmaceuticals, Technetium Tc 99m Lidofenin, Graft Survival physiology, Liver Transplantation methods, Portal System physiology
- Abstract
Background/purpose: Auxiliary liver transplantation is an attractive alternative for orthotopic liver transplantation in patients with certain inborn errors of metabolism of the liver in which complete resection of the liver is unnecessary or even contraindicated. Because in these diseases portal hypertension is mostly absent, finding a balance in portal blood distribution between native liver and graft is complicated. The objective of this study was to investigate requirements for long-term (180 days) graft survival in auxiliary partial heterotopic liver transplantation (APHLT) in a dog model., Methods: A metabolic defect was corrected in 26 dalmation dogs with a 60% beagle heterotopic auxiliary liver graft. Four groups of different portal inflow were studied. In the ligation group the portal vein to the host liver was ligated. In the split-flow group graft and host liver received separate portal inflow. In the banding group the distribution of the portal flow was regulated with an adjustable strapband and in the free-flow group the portal blood was allowed to flow randomly to host or graft liver., Results: Metabolic correction increased in all groups after transplantation from 0.19 +/- 0.02 to 0.70 +/- 0.05 (P< .0001) but remained significantly better in the ligation and split-flow groups (graft survival, 135 +/- 27 and 144 +/- 31 days). In the banding group metabolic correction decreased significantly after 70 days, and although the grafts kept some function for 155 +/- 14 days, in 4 of 6 dogs portal thrombosis was found. In the free-flow group, competition for the portal blood led to reduced correction within 12 days and total loss of function in 96 +/- 14 days. Graft function also was assessed with technetium (Tc) 99m dimethyl-iminodiacetic acid uptake. A good linear association between HIDA uptake and metabolic correction was observed (r = 0.74; P < .0005). Grafts that contributed more than 15% to the total uptake of HIDA showed biochemical correction. This indicates a critical graft mass of about 15% to 20% of the hepatocyte volume to correct this metabolic defect., Conclusion: Auxiliary partial heterotopic liver transplantation can be a valuable alternative treatment for inborn errors of hepatic metabolism if the native liver and the graft receive separate portal blood inflow. more...
- Published
- 1999
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24. Genetic susceptibility of the donor kidney contributes to the development of renal damage after syngeneic transplantation.
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Kouwenhoven EA, van Dokkum RP, Marquet RL, Heemann UW, de Bruin RW, IJzermans JN, and Provoost AP
- Subjects
- Albuminuria genetics, Animals, Blood Pressure physiology, Body Weight, Glomerulosclerosis, Focal Segmental, Hypertension, Renal genetics, Kidney pathology, Kidney Diseases pathology, Male, Myocardium pathology, Organ Size physiology, Rats, Rats, Inbred Strains, Transplantation, Isogeneic, Kidney Diseases genetics, Kidney Transplantation physiology, Tissue Donors
- Abstract
Solitary kidneys, especially in rats, appear vulnerable to develop functional and structural damage. However, differences in susceptibility exist between strains. It is not clear whether this is intrinsic to the kidney or due to environmental factors. Therefore, the aim of the present study was to investigate possible differences in genetic susceptibility for renal damage. By transplanting different rat donor kidneys into a normotensive, histocompatible recipient, the kidneys were exposed to the same blood pressure profiles, metabolic and hormonal environment. Kidneys from young adult hypertensive fawn-hooded (FHH) rats, a strain showing early onset renal damage, normotensive, renal damage-resistant August x Copenhagen-Irish (ACI), and (ACI x FHH) F1 donors were transplanted into male F1 recipients. The native kidneys of the recipients were removed 1 week after transplantation. The results were mutually compared and to their unilaterally nephrectomized littermates. Systolic blood pressure (SBP) and albuminuria (UaV) were determined at the time of transplantation and at 8 and 16 weeks. The histomorphologic analysis included the incidence of focal glomerulosclerosis (FGS), and determination of chronic transplant dysfunction according to the BANFF criteria. A negative impact of the transplantation technique in this syngeneic situation could not be detected as F1 transplants did not differ functionally and morphologically from their UNx controls. Transplanting an ACI kidney did not result in significant changes of SBP, UaV, and incidence of FGS compared to F1 transplants and ACI-UNx. In contrast, FHH kidneys did show a progressive increase of UaV and glomerulosclerosis and a significantly higher BANFF score, whereas the SBP did not differ from F1 transplants. The moderate hypertension seen in FHH did not travel with the kidney. Compared to the FHH-UNx rats, transplantation of a FHH kidney did significantly attenuate the increase of UaV and FGS. The susceptibility of the donor kidney appears to be an important factor in the development of chronic renal damage. This may play a role in the long-term functional changes seen after clinical renal transplantation. more...
- Published
- 1999
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25. Altered renal hemodynamics and impaired myogenic responses in the fawn-hooded rat.
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van Dokkum RP, Sun CW, Provoost AP, Jacob HJ, and Roman RJ
- Subjects
- Animals, Glomerulosclerosis, Focal Segmental pathology, Hemodynamics physiology, Kidney Glomerulus pathology, Male, Punctures, Rats, Renal Artery growth & development, Muscle Development, Muscle, Smooth, Vascular growth & development, Rats, Inbred Strains physiology, Renal Circulation physiology
- Abstract
The present study examined whether an abnormality in the myogenic response of renal arterioles that impairs autoregulation of renal blood flow (RBF) and glomerular capillary pressure (PGC) contributes to the development of renal damage in fawn-hooded hypertensive (FHH) rats. Autoregulation of whole kidney, cortical, and medullary blood flow and PGC were compared in young (12 wk old) FHH and fawn-hooded low blood pressure (FHL) rats in volume-replete and volume-expanded conditions. Baseline RBF, cortical and medullary blood flow, and PGC were significantly greater in FHH than in FHL rats. Autoregulation of renal and cortical blood flow was significantly impaired in FHH rats compared with results obtained in FHL rats. Myogenically mediated autoregulation of PGC was significantly greater in FHL than in FHH rats. PGC rose from 46 +/- 1 to 71 +/- 2 mmHg in response to an increase in renal perfusion pressure from 100 to 150 mmHg in FHH rats, whereas it only increased from 39 +/- 2 to 53 +/- 1 mmHg in FHL rats. Isolated perfused renal interlobular arteries from FHL rats constricted by 10% in response to elevations in transmural pressure from 70 to 120 mmHg. In contrast, the diameter of vessels from FHH rats increased by 15%. These results indicate that the myogenic response of small renal arteries is altered in FHH rats, and this contributes to an impaired autoregulation of renal blood flow and elevations in PGC in this strain. more...
- Published
- 1999
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26. Impaired autoregulation of renal blood flow in the fawn-hooded rat.
- Author
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Van Dokkum RP, Alonso-Galicia M, Provoost AP, Jacob HJ, and Roman RJ
- Subjects
- Animals, Blood Pressure physiology, Diuresis physiology, Hypertension physiopathology, Hypertension urine, Hypotension physiopathology, Kidney Glomerulus pathology, Male, Natriuresis physiology, Perfusion, Pressure, Proteinuria etiology, Rats, Rats, Inbred ACI, Rats, Inbred Strains, Reference Values, Homeostasis physiology, Renal Circulation physiology
- Abstract
The responses to changes in renal perfusion pressure (RPP) were compared in 12-wk-old fawn-hooded hypertensive (FHH), fawn-hooded low blood pressure (FHL), and August Copenhagen Irish (ACI) rats to determine whether autoregulation of renal blood flow (RBF) is altered in the FHH rat. Mean arterial pressure was significantly higher in conscious, chronically instrumented FHH rats than in FHL rats (121 +/- 4 vs. 109 +/- 6 mmHg). Baseline arterial pressures measured in ketamine-Inactin-anesthetized rats averaged 147 +/- 2 mmHg (n = 9) in FHH, 132 +/- 2 mmHg (n = 10) in FHL, and 123 +/- 4 mmHg (n = 9) in ACI rats. Baseline RBF was significantly higher in FHH than in FHL and ACI rats and averaged 9.6 +/- 0.7, 7.4 +/- 0.5, and 7.8 +/- 0.9 ml. min-1. g kidney wt-1, respectively. RBF was autoregulated in ACI and FHL but not in FHH rats. Autoregulatory indexes in the range of RPPs from 100 to 150 mmHg averaged 0.96 +/- 0.12 in FHH vs. 0.42 +/- 0.04 in FHL and 0.30 +/- 0.02 in ACI rats. Glomerular filtration rate was 20-30% higher in FHH than in FHL and ACI rats. Elevations in RPP from 100 to 150 mmHg increased urinary protein excretion in FHH rats from 27 +/- 2 to 87 +/- 3 microg/min, whereas it was not significantly altered in FHL or ACI rats. The percentage of glomeruli exhibiting histological evidence of injury was not significantly different in the three strains of rats. These results indicate that autoregulation of RBF is impaired in FHH rats before the development of glomerulosclerosis and suggest that an abnormality in the control of renal vascular resistance may contribute to the development of proteinuria and renal failure in this strain of rats. more...
- Published
- 1999
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27. Recoverability of renal function after relief of chronic partial upper urinary tract obstruction.
- Author
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Shokeir AA, Provoost AP, and Nijman RJ
- Subjects
- Biopsy methods, Enzymes urine, Humans, Kidney Diseases diagnostic imaging, Kidney Diseases surgery, Nephrostomy, Percutaneous methods, Radionuclide Imaging, Transforming Growth Factor beta metabolism, Ultrasonography, Doppler, Ureteral Obstruction diagnostic imaging, Ureteral Obstruction surgery, Kidney Diseases physiopathology, Recovery of Function, Ureteral Obstruction physiopathology
- Published
- 1999
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28. From segmental glomerulosclerosis to total nephron degeneration and interstitial fibrosis: a histopathological study in rat models and human glomerulopathies.
- Author
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Kriz W, Hosser H, Hähnel B, Gretz N, and Provoost AP
- Subjects
- Animals, Autopsy, Biopsy, Fibrosis, Humans, Male, Rats, Glomerulosclerosis, Focal Segmental pathology, Kidney Glomerulus pathology, Nephrons pathology
- Abstract
Background: Focal segmental glomerulosclerosis (FSGS) is consistently associated with tubular degeneration and interstitial fibrosis, altogether, accounting for the progressive decline in renal function. The mechanisms which link glomerular injury to tubulo-interstitial fibrosis are controversial. The present study describes the step-by-step sequence of histopathological events, i.e. the evolution of the injury from the initial lesion in the glomerulus to total nephron destruction., Methods: The investigation was performed in male hypertensive Fawn-hooded rats (6-, 9-, and 12-month-old) and 14-month-old Milan normotensive rats. The kidneys were fixed by in vivo perfusion and processed for structural investigation. Autopsy materials from human cases of focal segmental glomerulosclerosis and diabetic nephropathy were also examined., Results: FSGS as seen in rat models consists of collapsed and hyalinized capillaries and mesangial portions which are included within a synechia between the glomerular tuft and Bowman's capsule. In addition, a synechia generally contains glomerular capillaries which are perfused and continue to filter with the filtrate being delivered into the interstitium rather than into Bowman's capsular space. Such filtration creates a paraglomerular space on the outer aspect of the parietal epithelium. This space becomes separated from the interstitium by a dense layer of sheet-like fibroblast processes. Associated with the progression to global sclerosis, this space spreads around the entire circumference of a glomerulus; all 'sclerotic' tuft portions are eventually contained in this space. Starting from the urinary pole this process also involves the proximal tubule, initially by expanding the tubular basement membrane (TBM) and later, by separating the TBM from its epithelium, thus creating a peritubular space by misdirected filtrate spreading. Similar to the situation observed at the glomerulus this space becomes separated from the interstitium by a layer of fibroblast processes. The final degeneration of the nephron occurs via two pathways. Pathway I whereby development to global sclerosis is dominant or develops concurrently with tubular degeneration, eventually terminating in global and cylindrical remnants of extracellular matrix surrounded by abundant fibrous tissue. Pathway II where the degeneration of the tubule is ahead of damage progression in the glomerulus leading to atubular glomerular cysts., Conclusion: The present study suggests that severely injured glomeruli may continue to filter with the filtrate spreading along interstitial routes. Fluid added locally to the interstitium from such 'extraterritorial' glomerular capillaries probably is quite different in quantity and composition compared to that from interstitial capillaries. We propose that this kind of abnormal addition of fluid to the interstitium is the essential mechanism accounting for interstitial progression of the disease. Similar histopathological phenomena in human kidneys with focal segmental glomerulosclerosis suggest that the pathogenetic pathways defined in the rat models operate in human disease as well. more...
- Published
- 1998
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29. Susceptibility genes for end-organ damage. New strategies to understand diabetic and hypertensive nephropathy.
- Author
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Broeckel U, Shiozawa M, Kissebah AH, Provoost AP, and Jacob HJ
- Subjects
- Animals, Disease Models, Animal, Humans, Diabetic Nephropathies genetics, Genetic Predisposition to Disease, Hypertension complications, Kidney Failure, Chronic genetics
- Published
- 1998
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30. Genetic control of susceptibility for renal damage in hypertensive fawn-hooded rats.
- Author
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Brown DM, Van Dokkum RP, Korte MR, McLauglin MG, Shiozawa M, Jacob HJ, and Provoost AP
- Subjects
- Angiotensin-Converting Enzyme Inhibitors therapeutic use, Animals, Blood Pressure, Disease Progression, Disease Susceptibility, Female, Follow-Up Studies, Genetic Linkage genetics, Glomerulosclerosis, Focal Segmental complications, Glomerulosclerosis, Focal Segmental urine, Hypertension, Renal complications, Hypertension, Renal physiopathology, Male, Phenotype, Proteinuria complications, Proteinuria urine, Rats, Rats, Inbred Strains, Renal Insufficiency urine, Sex Characteristics, Glomerulosclerosis, Focal Segmental genetics, Hypertension, Renal genetics, Proteinuria genetics
- Published
- 1998
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31. Development of vascular pole-associated glomerulosclerosis in the Fawn-hooded rat.
- Author
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Kriz W, Hosser H, Hähnel B, Simons JL, and Provoost AP
- Subjects
- Animals, Arterioles physiopathology, Arterioles ultrastructure, Kidney pathology, Kidney ultrastructure, Kidney Diseases pathology, Kidney Diseases physiopathology, Kidney Glomerulus physiopathology, Kidney Glomerulus ultrastructure, Male, Rats, Rats, Inbred Strains, Rats, Mutant Strains, Rats, Wistar, Sclerosis pathology, Sclerosis physiopathology, Glomerulosclerosis, Focal Segmental physiopathology, Kidney Glomerulus blood supply
- Abstract
Fawn-hooded hypertensive (FHH) rats constitute a spontaneous model of chronic renal failure with early systemic and glomerular hypertension, proteinuria, and development of focal and segmental glomerulosclerosis. The goal of the present study was to elucidate a step-by-step sequence of histopathologic events leading from an initial glomerular injury to segmental sclerosis. Segmental sclerosis in the FHH rat is consistently associated with the glomerular vascular pole. The initial injury involves the expansion of primary branches of the afferent arteriole. Apposition of those capillaries to Bowman's capsule, together with the degeneration and detachment of corresponding podocytes, allows parietal cells to attach to the naked glomerular basement membrane of this capillary, i.e., allows the formation of a tuft adhesion to Bowman's capsule. The adhesion enlarges to a broad synechia by encroaching to neighboring capillaries, apparently based on progressive podocyte degeneration at the flanks of the adhesion. Capillaries inside the adhesion--before undergoing collapse or hyalinization--appear to stay perfused for some time and to maintain some kind of filtration misdirected toward the cortical interstitium. Thereby, a prominent paraglomerular space comes into existence, enlarging in parallel with the adhesion. Toward the cortical interstitium this space is delimited by a layer of sheetlike fibroblast processes, which has obviously been assembled in response to the formation of this space. Toward the urinary space, the paraglomerular space is demarcated by the parietal epithelium and by the interface between the adhesion and the "intact" tuft remnant. Thus, the sclerotic tuft portions all become enclosed within the paraglomerular space. more...
- Published
- 1998
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32. Genetic differences define severity of renal damage after L-NAME-induced hypertension in rats.
- Author
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Van Dokkum RP, Jacob HJ, and Provoost AP
- Subjects
- Animals, Autopsy, Blood Pressure physiology, Body Weight physiology, Creatinine metabolism, Glomerulosclerosis, Focal Segmental epidemiology, Humans, Hypertension, Renal chemically induced, Hypertension, Renal physiopathology, Incidence, Infant, NG-Nitroarginine Methyl Ester adverse effects, Rats, Rats, Inbred Strains, Regression Analysis, Renal Insufficiency genetics, Renal Insufficiency physiopathology, Severity of Illness Index, Species Specificity, Survival, Systole, Hypertension, Renal complications, Renal Insufficiency etiology
- Abstract
Genetic factors are important in determining the susceptibility to renal damage. In a backcross of the hypertensive and proteinuric fawn-hooded Erasmus University Rotterdam (FHH/EUR) rat with the normotensive, nonproteinuric August Copenhagen Irish (ACI/EUR) rat, two genes (denoted Rf-1 and Rf-2) were genetically mapped for parameters of functional and structural renal damage. The aim of the present study was to investigate the susceptibility to functional and structural renal damage in heterozygous (FHH X ACI) F1 rats compared with the parental FHH and ACI strains at similar levels of systolic BP (SBP). BP elevation was induced by chronic treatment with NG-nitro-L-arginine methyl ester (L-NAME) in either a low dose (LD, 75 to 100 mg/L) or a high dose (HD, 175 to 250 mg/L) in the drinking fluid. Survival of FHH rats and, to a lesser extent, F1 rats, was adversely affected by L-NAME treatment. All ACI rats except for one ACI-HD animal survived. In all strains, L-NAME caused a dose-dependent increase in SBP. At similar levels of SBP, the increase in functional renal damage, as indicated by the level of albuminuria, was higher in F1 compared with ACI, but lower compared with FHH. The same differences were found for the level of structural renal damage, as indicated by the incidence of glomerulosclerosis. Both the SBP and the average BP burden (SBP-Av), defined as SBP averaged over the period of follow-up, directly correlated with the level of albuminuria and incidence of glomerulosclerosis in all strains. However, the increase in the degree of renal damage per mmHg increase in SBP or SBP-Av was significantly higher in the F1 rats compared with ACI, but lower compared with FHH rats. Values for these F1 rats were closer to the ACI rats than to values for the FHH rats and increased above an SBP level of 180 mmHg. The F1 rats, being heterozygous for Rf-1 and Rf-2, as well as for other potential genes responsible for renal disease, were largely, but not completely, protected from hypertension-induced renal damage. It is concluded that complete susceptibility to hypertension-associated renal damage in rats primarily depends on the presence of predisposing genes for renal failure even after a significant increase in BP. more...
- Published
- 1998
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33. Difference in susceptibility of developing renal damage in normotensive fawn-hooded (FHL) and August x Copenhagen Irish (ACI) rats after N(omega)-nitro-L-arginine methyl ester induced hypertension.
- Author
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van Dokkum RP, Jacob HJ, and Provoost AP
- Subjects
- Albuminuria chemically induced, Animals, Disease Susceptibility, Kidney abnormalities, Male, Rats, Rats, Inbred ACI, Regression Analysis, Species Specificity, Enzyme Inhibitors toxicity, Hypertension chemically induced, Kidney Diseases genetics, NG-Nitroarginine Methyl Ester toxicity, Nitric Oxide Synthase antagonists & inhibitors
- Abstract
Previous studies using the fawn-hooded hypertensive (FHH) rat have indicated that genetic factors appear to be important in determining the susceptibility to develop renal damage. This was further investigated by comparing the effects of N(omega)-nitro-L-arginine methyl ester (L-NAME) induced hypertension on functional and structural renal damage in two normotensive strains, the resistant August x Copenhagen Irish rat (ACI) and the normotensive fawn-hooded (FHL) rat, which also appears to carry a susceptibility locus for renal failure. Male rats were studied during chronic treatment with L-NAME in either a low dose (LD, 75 to 100 mg/L drinking fluid) or a high dose (HD, 175 to 250 mg/L). Survival of FHL rats was adversely affected by L-NAME treatment. All FHL-HD and 6 of 14 FHL-LD rats died before the end of the 11 weeks of follow-up, whereas all treated ACI rats except for one ACI-HD animal survived. In both strains, L-NAME caused a dose dependent increase in systolic blood pressure (SBP). However, at similar levels of SBP, the increase in albuminuria (UaV) was significantly higher in FHL compared with ACI, as was the incidence of glomerulosclerosis (GS). Both the SBP and the blood pressure burden (SBP-Av), defined as SBP averaged over the period of follow-up, directly correlated with UaV and GS in both strains. However, the increase in the degree of renal damage per millimeter of mercury increase in SBP or SBP-Av was significantly higher in the FHL than in the ACI rats. Our findings clearly show that FHL rats are more susceptible to developing renal damage after induction of hypertension by chronic L-NAME treatment. We conclude that there is an interaction between blood pressure and the genetic susceptibility to renal disease in the FHL rat. more...
- Published
- 1997
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34. Renal Doppler ultrasonography in children with equivocal obstructive uropathy: effect of intravenous normal saline fluid load and frusemide.
- Author
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Shokeir AA, Provoost AP, El-Azab M, Dawaba M, Shokeir MA, and Nijman RJ
- Subjects
- Child, Child, Preschool, Dilatation, Pathologic diagnostic imaging, Female, Fluid Therapy methods, Glomerular Filtration Rate drug effects, Humans, Hydronephrosis therapy, Infant, Infusions, Intravenous, Male, Radioisotope Renography, Sodium Chloride administration & dosage, Ultrasonography, Diuretics administration & dosage, Furosemide administration & dosage, Hydronephrosis diagnostic imaging
- Abstract
Objective: To study the effect of hyperhydration with normal saline and frusemide on the renal resistive index (RI) in children with equivocal obstructive uropathy., Patients and Methods: Twelve children (24 kidneys) with unilateral or bilateral hydronephrosis underwent isotopic diuretic renography and Doppler ultrasonography. All children had equivocal obstruction of the hydronephrotic kidneys with half-time drainage (T/2) values of 10-20 min. Doppler studies were carried out both at baseline and after the infusion of normal saline and frusemide., Results: Of the 24 kidneys, five were normal and 19 were hydronephrotic; compared with normal kidneys, the hydronephrotic units had a significantly lower glomerular filtration rate (GFR) and longer T/2. At baseline, the mean RI values of normal and hydronephrotic kidneys were not significantly different (0.70, SD 0.03 and 0.71, SD 0.04, respectively). After the infusion of saline and frusemide, the mean RI of hydronephrotic kidneys (0.67, SD 0.07) was significantly (P = 0.01) higher than that of normal kidneys (0.60, SD 0.02), but the response of RI in hydronephrotic kidneys was variable. Based on the RI at baseline and after infusion, hydronephrotic kidneys could be categorized into three groups. Group 1 (n = 6) had an RI < 0.7 before and after infusion, group 2 (n = 6) had a baseline RI > 0.7 and < 0.7 after infusion, and in group 3 (n = 7) both RIs were > 0.7. Kidneys in group 3 had the lowest GFR and the highest T/2 values. Five of these seven hydronephrotic kidneys eventually had deteriorating GFRs requiring surgical correction; the GFR of the remaining hydronephrotic kidneys remained stable., Conclusion: In children with equivocal obstructive uropathy based on diuretic renography, the determination of RI before and after infusion of normal saline and frusemide could be helpful in distinguishing obstructed from non-obstructed kidneys. more...
- Published
- 1997
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35. Resistive index in obstructive uropathy.
- Author
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Shokeir AA, Provoost AP, and Nijman RJ
- Subjects
- Adult, Child, Child, Preschool, Dilatation, Pathologic, False Negative Reactions, False Positive Reactions, Forecasting, Humans, Radiography, Sensitivity and Specificity, Ultrasonography, Doppler, Ultrasonography, Interventional, Ureteral Obstruction diagnostic imaging, Ureteral Obstruction diagnosis
- Published
- 1997
- Full Text
- View/download PDF
36. Partial ureteral obstruction: role of renal resistive index in stages of obstruction and release.
- Author
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Shokeir AA, Nijman RJ, el-Azab M, and Provoost AP
- Subjects
- Animals, Dogs, Male, Renal Circulation, Ultrasonography, Doppler, Ureteral Obstruction diagnosis, Urodynamics, Ureteral Obstruction physiopathology
- Abstract
Objectives: To study the changes in renal resistive index (RI) and renal function before and after release of different grades of partial unilateral ureteral obstructions., Methods: Ten dogs were subjected to right partial ureteral obstruction. Grade 1 (mild) obstruction was applied to 5 dogs (group A) and grade 3 (moderate and severe) obstruction was applied to the other 5 dogs (group B). Obstruction was maintained for 8 weeks, followed by release of obstruction. All dogs were subjected to excretory urography, technetium-99m mercaptoacetyltriglycine diuretic renography with calculation of half-time drainage (T1/2), and bilateral renal Doppler ultrasonography before the start of the experiment, after 8 weeks of obstruction, and every 2 weeks during the 8 weeks after release of obstruction., Results: In both groups, after induction of right ureteral obstruction, there was a dramatic decrease of effective renal plasma flow (ERPF), increase of RI, and increase of T1/2 of the right kidney. Relief of obstruction was associated with normalization of T1/2, reversal of RI, and recovery of ERPF to near basal values. No correlation was found between ERPF at the end of the recovery period and the functional parameters (T1/2, RI, or ERPF) of the obstructed kidney before release of obstruction., Conclusions: (1) Unilateral partial ureteral obstruction produces an elevation of RI and T1/2 and a fall in ERPF of the corresponding kidney. (2) After relief of function is regained with associated reversal of RI. (3) Functional parameters (T1/2, RI, or ERPF) of the obstructed kidney do not predict the recovery of ERPF after release of obstruction. (4) Rapid reversal of a previously elevated RI is an early indicator of recoverability of renal function after relief of ureteral obstruction. more...
- Published
- 1997
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37. Partial ureteral obstruction: effect of intravenous normal saline and furosemide upon the renal resistive index.
- Author
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Shokeir AA, Nijman RJ, el-Azab M, and Provoost AP
- Subjects
- Animals, Dogs, Injections, Intravenous, Male, Ultrasonography, Doppler, Ureteral Obstruction diagnostic imaging, Diuretics administration & dosage, Furosemide administration & dosage, Kidney drug effects, Kidney physiopathology, Sodium Chloride administration & dosage, Ureteral Obstruction physiopathology
- Abstract
Objective: To investigate the effect of intravenous normal saline fluid load, with and without furosemide, upon the renal resistive index (RI) of obstructed and nonobstructed kidneys., Methods: Right partial ureteral obstruction was induced in 10 dogs. Grade 1 (mild) obstruction was performed in 5 dogs (group A), and grade 3 (severe) obstruction was carried out to the remaining 5 dogs (group B). Evaluation by Doppler ultrasonography was performed before induction of ureteral obstruction and by the end of the 8th week of obstruction. Every obstructed animal was subjected to bilateral renal Doppler ultrasonography 3 times in one setting: 1) before infusion of normal saline, 2) 30-60 minutes after intravenous infusion of normal saline (15 ml./kg.) given in a rate of 1 ml./kg./min. and 3) 10 minutes after admission of furosemide (1 mg./kg.)., Results: After induction of right partial ureteral obstruction, there was a significant increase of the RI of the right kidney and a significant decrease of the RI of the left kidney compared to baseline RI in both groups. Infusion of normal saline and administration of furosemide caused a further significant increase of the RI of the obstructed kidney and a further significant decrease of the RI in the nonobstructed kidney in both groups., Conclusion: In unilateral partial ureteral obstruction, addition of intravenous normal saline and furosemide cause the RI to increase in obstructed kidney and to decrease in nonobstructed kidney. Such a divergent response may be useful for the development of a pharmacologically challenged Doppler examination to diagnose better potentially obstructed kidneys. more...
- Published
- 1997
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38. Angiotensin-converting enzyme inhibition in the prevention and treatment of chronic renal damage in the hypertensive fawn-hooded rat.
- Author
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Verseput GH, Provoost AP, Braam BB, Weening JJ, and Koomans HA
- Subjects
- Age Factors, Albuminuria drug therapy, Albuminuria etiology, Albuminuria prevention & control, Angiotensin-Converting Enzyme Inhibitors administration & dosage, Animals, Blood Pressure drug effects, Glomerulosclerosis, Focal Segmental drug therapy, Glomerulosclerosis, Focal Segmental etiology, Glomerulosclerosis, Focal Segmental prevention & control, Hypertension drug therapy, Hypertension physiopathology, Kidney Failure, Chronic etiology, Male, Rats, Angiotensin-Converting Enzyme Inhibitors pharmacology, Hypertension complications, Kidney Failure, Chronic drug therapy, Kidney Failure, Chronic prevention & control
- Abstract
The spontaneously hypertensive fawn-hooded rat (FHH) develops accelerated albuminuria and focal glomerular sclerosis (FGS), leading to ESRD and shortening of lifespan. The FHH is characterized by moderate systemic hypertension, a relatively low afferent to efferent arteriolar resistance ratio, and glomerular hypertension. The FHH study presented here was designed to examine the efficacy of early-onset, late-onset, or early-temporary angiotensin I-converting enzyme inhibition (ACE-i) in ameliorating long-term hypertension and FGS, and improving survival, as well as to relate its protective efficacy to preexistent FGS and to reduction of glomerular pressure (PGC) Untreated rats developed hypertension and high PGC, and all (N = 22) except one died of ESRD within the 72-wk follow-up period. Early-onset (at 7 wk of age) ACE-i prevented development of systemic and glomerular hypertension, and it largely prevented proteinuria and FGS; all rats survived throughout the follow-up period. Rats treated with late-onset (22 wk) ACE-i were hypertensive and proteinuric at the start of ACE-i, and they showed beginning FGS. ACE-i corrected the hypertension, albuminuria, and PGC but could not fully prevent some hypertension, albuminuria, and FGS at the later stage. Early-temporary (7 to 22 wk) ACE-i adequately controlled blood pressure and development of FGS during therapy, but after withdrawal of ACE-i, systemic and glomerular hypertension developed as in untreated animals. This regimen postponed but did not control FGS development and early mortality. The results of this study indicate that: (1) early-onset ACE-i very effectively protects against development of renal damage in the FHH; (2) this protection is associated with normalization of the elevated glomerular capillary pressure; (3) ACE-i cannot completely prevent further development of previously established FGS, despite lowering glomerular capillary pressure; (4) early-temporary ACE-i has no long-term controlling effect on arterial and glomerular pressure, and it cannot control development of FGS. more...
- Published
- 1997
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39. Hyperlipidemia is secondary to proteinuria and is completely normalized by angiotensin-converting enzyme inhibition in hypertensive fawn-hooded rats.
- Author
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Verseput GH, Provoost AP, van Tol A, Koomans HA, and Joles JA
- Subjects
- Angiotensin-Converting Enzyme Inhibitors therapeutic use, Animals, Antihypertensive Agents pharmacology, Antihypertensive Agents therapeutic use, Apolipoproteins blood, Blood Pressure drug effects, Body Weight drug effects, Cholesterol blood, Creatinine blood, Disease Models, Animal, Hyperlipidemias drug therapy, Hyperlipidemias metabolism, Hypertension complications, Lisinopril pharmacology, Lisinopril therapeutic use, Male, Osmotic Pressure drug effects, Proteinuria drug therapy, Proteinuria metabolism, Rats, Rats, Inbred Strains, Statistics as Topic, Triglycerides blood, Angiotensin-Converting Enzyme Inhibitors pharmacology, Hyperlipidemias etiology, Hypertension metabolism, Proteinuria complications
- Abstract
Two substrains of the fawn-hooded (FH) rat have been developed, one of which develops progressive hypertension and proteinuria, the FHH, and one which shows little increase in blood pressure and no renal damage, the FHL. Other hypertensive rodent models show primary metabolic disturbances before the development of renal damage, notably hypertriglyceridemia, which may also contribute to progression of renal disease. In this study we evaluated whether hyperlipidemia is a primary disturbance in FHH, or only occurs secondary to proteinuria. Lipid levels were determined before and after development of proteinuria, and compared to those found in age-matched FHL. We also determined whether reducing proteinuria with lisinopril would normalize lipid levels in aging FHH. At 4 weeks of age, proteinuria was very low (2-3 mg/day) in both FHH and FHL. While proteinuria increased steadily in aging FHH, reaching 350 +/- 62 mg/day at 40 weeks, much less increase was observed in FHL over the same period (32 +/- 5 mg/day at 40 weeks). Blood pressure was markedly higher in adult FHH than in FHL (158 +/- 2 vs. 129 +/- 2 mm Hg, p < 0.01). In 4-week-old FHL and FHH, plasma cholesterol levels were similar. Subsequently, cholesterol increased in FHH, reaching 3.4 +/- 0.9 mmol/l at 40 weeks, whereas cholesterol was barely affected by aging in FHL (2.1 +/- 0.2 mmol/l at 40 weeks). At 4 weeks, triglyceride levels were lowest in FHH. Subsequently, triglycerides increased in FHH, reaching 3.5 +/- 1.5 mmol/l at 40 weeks, as compared to 1.3 +/- 0.2 mmol/l in FHL. Besides a transient increase in triglyerides in lisinopril-treated FHH at 11 weeks, increments in blood pressure, proteinuria, cholesterol, triglycerides and apolipoproteins A-I, B and E aging FHH were effectively prevented by lisinopril. These data strongly suggest that there is no primary difference in lipid metabolism between FHH and FHL and that changes in plasma lipids in FHH as compared to FHL are all secondary to proteinuria. more...
- Published
- 1997
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40. Partial ureteric obstruction: a study of Doppler ultrasonography and diuretic renography in different grades and durations of obstruction.
- Author
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Shokeir AA, Nijman RJ, el-Azab M, and Provoost AP
- Subjects
- Animals, Blood Flow Velocity, Dogs, Kidney blood supply, Male, Radiography, Radioisotope Renography, Ultrasonography, Doppler, Ureteral Obstruction diagnostic imaging, Ureteral Obstruction physiopathology
- Abstract
Objectives: To study the changes in renal resistive index (RI) and renal function with time during different grades of partial unilateral ureteric obstruction, and to determine the correlation between the ultrasonographic and renographic findings., Materials and Methods: Ten dogs underwent right partial ureteric obstruction: grade 1 (mild) obstruction was applied in five dogs (group A) and grade 3 (moderate and severe) obstruction in the other five (group B). All dogs were assessed using excretory urography, diuretic renography with the calculation of half-time drainage (T 1/2) and bilateral renal Doppler ultrasonography before the experiment began, after one week of obstruction, and every 2 weeks during 8 weeks of obstruction., Results: In both groups, after the induction of right ureteric obstruction, there was a progressive decrease of effective renal plasma flow (ERPF) and a progressive increase of the RI of the right kidney at the end of the first and second weeks of obstruction, with an almost stable value thereafter. The decrease of ERPF and the increase of RI in the right kidney were correlated with the degree of obstruction. There was also a dramatic increase of T 1/2 of the right kidney that correlated with the degree of obstruction. Concomitantly, there was a significant compensatory increase of ERPF and a significant decrease of the RI of the left kidney in both groups. The compensatory increase in CRPF limited the loss in total ERPF in both groups. The contribution of obstructed kidney to the total ERPF was significantly reduced in both groups. At the end of the eighth week, taking all kidneys together, there was a statistically significant negative correlation between the ERPF and RI, and between ERPF and T 1/2 and a positive correlation between T 1/2 and RI., Conclusions: Unilateral partial ureteric obstruction increased the RI and T 1/2 and decreased the ERPF of the corresponding kidney, together with a decrease of RI and an increase in ERPF of the contralateral kidney. The more severe the obstruction, the greater the increase in RI and T 1/2 and the decrease in ERPF. After the obstruction stabilized, RI and T 1/2 were positively correlated. more...
- Published
- 1996
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41. The angiotensin receptor antagonist, irbesartan, reduces renal injury in experimental chronic renal failure.
- Author
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Ziai F, Ots M, Provoost AP, Troy JL, Rennke HG, Brenner BM, and Mackenzie HS
- Subjects
- Animals, Irbesartan, Kidney Failure, Chronic drug therapy, Kidney Glomerulus drug effects, Kidney Glomerulus physiopathology, Nephrectomy, Rats, Rats, Inbred SHR, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors pharmacology, Antihypertensive Agents pharmacology, Biphenyl Compounds pharmacology, Blood Pressure drug effects, Enalapril pharmacology, Proteinuria prevention & control, Tetrazoles pharmacology
- Abstract
The effects of chronic treatment with the specific AT1 angiotensin receptor antagonist, irbesartan, or the angiotensin converting enzyme inhibitor, enalapril, were assessed in uninephrectomized fawn-hooded hypertensive rats (FHH) and compared with vehicle treatment. Three days after uninephrectomy, irbesartan (240 mg/liter), enalapril (80 mg/liter) or vehicle were administered via the drinking water. Systolic blood pressure (SBP) and protein excretion rates (UprotV) were determined monthly. In rats receiving irbesartan (N = 7) and enalapril (N = 6) SBP (132 +/- 3 mm Hg and 133 +/- 6, respectively) was essentially normalized at 12 weeks when compared with vehicle (169 +/- 6 mm Hg (N = 6); all comparisons were P < 0.05 by ANOVA). Similarly, proteinuria was lower in irbesartan (44 +/- 12 mg/day) and enalapril (19 +/- 2) groups versus vehicle (123 +/- 10 mg/day). Treatment with both drugs was associated with marked reduction in glomerulosclerosis at 12 weeks (both < 5% vs. vehicle, 43 +/- 9%) without effect on glomerular volume. In identically prepared rats, glomerular capillary hydraulic pressure (PGC, estimated from stop-flow pressure, Psf) was lower in FHH receiving irbesartan (58 +/- 1 mm Hg, N = 6) or enalapril (54 +/- 2, N = 6) than in vehicle-treated rats, in whom PGC was greatly elevated (68 +/- 2 mm Hg; N = 7). Despite this, GFR and single nephron GFR were well maintained. These data support a critical role for AT1 receptor-mediated, angiotensin-dependent processes in the pathogenesis of hypertension in FHH, and further implicate elevated PGC as a major determinant of glomerular injury in this model. more...
- Published
- 1996
42. Renal Doppler ultrasound in children with obstructive uropathy: effect of intravenous normal saline fluid load and furosemide.
- Author
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Shokeir AA, Provoost AP, el-Azab M, Dawaba M, and Nijman RJ
- Subjects
- Child, Child, Preschool, False Negative Reactions, False Positive Reactions, Female, Hemodynamics, Humans, Hydronephrosis etiology, Hydronephrosis physiopathology, Infant, Infusions, Intravenous, Injections, Intravenous, Male, Reproducibility of Results, Sensitivity and Specificity, Ultrasonography, Doppler, Ureteral Obstruction etiology, Ureteral Obstruction physiopathology, Diuretics administration & dosage, Furosemide administration & dosage, Hydronephrosis diagnostic imaging, Sodium Chloride administration & dosage, Ureteral Obstruction diagnostic imaging
- Abstract
Purpose: We studied the effect of hyperhydration with normal saline and furosemide on renal resistive index in children with obstructive uropathy., Materials and Methods: 99mTechnetium-mercaptoacetyltriglycine diuretic renography and Doppler ultrasound were done in 27 children (54 renal units) with unilateral or bilateral hydronephrosis. Doppler studies were performed at baseline, and after infusion of normal saline and administration of furosemide. Half-time drainage, considered the gold standard for the diagnosis of renal obstruction, was compared to resistive index., Results: There was a positive correlation between half-time and resistive index on both Doppler studies. With a resistive index of 0.70 as the critical value for predicting renal obstruction 82 versus 100% sensitivity (p < 0.006), 63 versus 94% specificity (p < 0.04) and 76 versus 98% overall accuracy (p < 0.0005) were obtained for Doppler studies at baseline and after induced diuresis, respectively. All children with false-positive results were younger than age 4 years., Conclusions: Doppler ultrasonography after hyperhydration with normal saline and furosemide is an accurate method for diagnosing renal obstruction in children. It is more sensitive, specific and accurate than baseline Doppler studies. more...
- Published
- 1996
- Full Text
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43. Stability and leakiness: opposing challenges to the glomerulus.
- Author
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Kriz W, Kretzler M, Provoost AP, and Shirato I
- Subjects
- Animals, Biological Transport physiology, Kidney Glomerulus cytology, Kidney Glomerulus ultrastructure, Kidney Glomerulus metabolism
- Abstract
The complex architecture of the glomerular tuft is stabilized by several mechanisms. The basic system consists of the GBM and the mesangium maintaining the branching pattern of the capillary network. Superimposed are the podocytes, which appear to take effect by two mechanisms. First, podocytes contribute to the stabilization of the capillary folding pattern by supporting the angles between neighboring capillaries. Second, podocyte foot processes fixed to the outer aspect of the GBM probably function as contractile patches counteracting the elastic distension of the GBM. Simultaneously, the pattern of foot process interdigitation underlies the elaboration of a filtration slit and is thus pivotal for the high hydraulic permeability and the specificity of the glomerular filter. The loss of this pattern-commonly termed "foot process effacement" or "foot process fusion"-is frequently found in pathological situations and results in a decrease in permeability and impairment in specificity. On the other hand, foot process effacement is associated with prominent hypertrophy of the contractile apparatus of podocytes, suggesting an increased ability to generate forces counteracting capillary expansion. Thus, foot process effacement appears as an adaptive change in podocyte phenotype giving priority to the support function of podocytes for the prize of reducing the specific permeability. more...
- Published
- 1996
- Full Text
- View/download PDF
44. Renal Doppler ultrasound in children with normal upper urinary tracts: effect of fasting, hydration with normal saline, and furosemide administration.
- Author
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Shokeir AA, Provoost AP, el-Azab M, Dawaba M, and Nijman RJ
- Subjects
- Child, Child, Preschool, Humans, Male, Ultrasonography, Doppler, Diuretics pharmacology, Fasting, Furosemide pharmacology, Kidney diagnostic imaging, Kidney drug effects, Sodium Chloride pharmacology
- Abstract
Objectives: To study the age dependency of renal resistive index (RI) and to study the effect on the renal RI of fasting, intravenous infusion of normal saline, and administration of furosemide in children with normal upper urinary tracts., Methods: The study included 28 nonobstructed renal units in 15 boys ranging in age from 3 to 11 years. Diuretic renography and Doppler ultrasonography were attempted in all children. Doppler ultrasonography was carried out under three different conditions: fasting state, 30 to 60 minutes after intravenous infusion of normal saline (15 mL/kg), and 10 minutes after administration of furosemide (1 mg/kg; maximum, 40 mg)., Results: There was an inverse correlation between age and RI of both renal units under the three conditions of Doppler studies. At fasting state mean RI was 0.70 +/- 0.04, whereas 15 of 28 renal units (54%) had an RI of 0.70 or higher. Intravenous infusion of normal saline significantly decreased the RI to 0.63 +/- 0.04 (P < 0.000001). Injection of furosemide caused a further significant decrease of RI from 0.63 +/- 0.04 to 0.60 +/- 0.04 (P < 0.002)., Conclusions: The renal RI in healthy children is age dependent. In the fasting state, 54% of nonobstructed renal units in children have an RI of 0.70 or higher. Intravenous infusion of normal saline and administration of furosemide can independently cause a significant decrease of the RI in nonobstructed renal units in children. more...
- Published
- 1996
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- View/download PDF
45. Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat.
- Author
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Brown DM, Provoost AP, Daly MJ, Lander ES, and Jacob HJ
- Subjects
- Animals, Base Sequence, Chromosome Mapping, DNA Primers chemistry, Female, Genetic Linkage, Male, Molecular Sequence Data, Proteinuria genetics, Rats, Rats, Inbred Strains, Hypertension genetics, Rats, Mutant Strains genetics, Renal Insufficiency genetics
- Abstract
Hypertension, diabetes and hyperlipidemia are risk factors for life-threatening complications such as end-stage renal disease, coronary artery disease and stroke. Why some patients develop complications is unclear, but only susceptibility genes may be involved. To test this notion, we studied crosses involving the fawn-hooded rat, an animal model of hypertension that develops chronic renal failure. Here, we report the localization of two genes, Rf-1 and Rf-2, responsible for about half of the genetic variation in key indices of renal impairment. In addition, we localize a gene, Bpfh-1, responsible for about 26% of the genetic variation in blood pressure. Rf-1 strongly affects the risk of renal impairment, but has no significant effect on blood pressure. Our results show that susceptibility to a complication of hypertension is under at least partially independent genetic control from susceptibility to hypertension itself. more...
- Published
- 1996
- Full Text
- View/download PDF
46. A frequent pathway to glomerulosclerosis: deterioration of tuft architecture-podocyte damage-segmental sclerosis.
- Author
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Kriz W, Kretzler M, Nagata M, Provoost AP, Shirato I, Uiker S, Sakai T, and Lemley KV
- Subjects
- Animals, Glomerulosclerosis, Focal Segmental physiopathology, Humans, Kidney Glomerulus injuries, Rats, Glomerulosclerosis, Focal Segmental pathology, Kidney Glomerulus pathology
- Abstract
Lesions in glomerular architecture include mesangial expansion, capillary ballooning, capillary unfolding and microaneurysm formation. Such lesions appear to develop in response to mechanical overextension. A frequent pathway to segmental glomerulosclerosis starts from capillary ballooning and unfolding. Podocytes supporting those deranged capillaries are exposed to increased mechanical stress. This may lead to podocyte injury terminating in detachments from the GBM. Naked GBM areas at peripheral capillary loops allow the attachment of parietal cells to the GBM, i.e. the formation of a tuft adhesion to Bowman's capsule. An adhesion has a strong tendency to progress to segmental sclerosis. more...
- Published
- 1996
- Full Text
- View/download PDF
47. [Long-term follow-up study of persons with a solitary kidney].
- Author
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Provoost AP
- Subjects
- Adult, Aged, Aged, 80 and over, Aging physiology, Child, Glomerular Filtration Rate, Humans, Kidney physiology, Kidney Diseases surgery, Kidney Transplantation, Longitudinal Studies, Middle Aged, Nephrectomy, Risk Factors, Kidney abnormalities
- Published
- 1995
48. Proteinuria and impaired glomerular permselectivity in uninephrectomized fawn-hooded rats.
- Author
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Oliver JD 3rd, Simons JL, Troy JL, Provoost AP, Brenner BM, and Deen WM
- Subjects
- Albuminuria, Animals, Blood Pressure, Enalapril therapeutic use, Glomerular Filtration Rate, Glomerulosclerosis, Focal Segmental physiopathology, Hemodynamics, Hypertension physiopathology, Hypertension prevention & control, Kidney blood supply, Male, Proteinuria prevention & control, Rats, Rats, Mutant Strains, Kidney Glomerulus physiopathology, Nephrectomy, Proteinuria physiopathology
- Abstract
Previous studies of glomerular permselectivity have indicated that both size selectivity and charge selectivity changes play a role in the pathogenesis of proteinuria. In this study, we measured Ficoll sieving coefficients, hemodynamic parameters, and urinary protein excretion rates in the FHH strain of fawn-hooded rats. These animals spontaneously develop systemic and glomerular hypertension, proteinuria, and focal and segmental glomerulosclerosis at a relatively young age. Three groups of FHH rats were studied: two-kidney controls (2K), untreated uninephrectomized rats (CON-NX), and uninephrectomized rats treated with the angiotensin I converting enzyme inhibitor enalapril (ENA-NX). CON-NX rats had higher glomerular transcapillary pressures (delta P) and higher urinary excretion rates of both total protein (UpV) and albumin (UaV) than did 2K rats, whereas treatment with enalapril prevented both glomerular hypertension and the increased proteinuria. Ficoll sieving coefficients were significantly higher in both groups of NX rats compared with 2K rats only for Stokes-Einstein radii (rs) > or = 46 A. Fits of sieving data to pore models showed a small increase in the number of large, nonselective pores in NX, which was not prevented by enalapril treatment. Total clearances of Ficoll with rs = 36 A (the size of albumin) in CON-NX and ENA-NX groups were unchanged compared with 2K animals. In contrast, UaV in CON-NX rats was more than six times that of 2K and ENA-NX rats. Across groups, UpV, UaV, and the ratio (UaV)/(UpV) all correlated strongly with delta P.(ABSTRACT TRUNCATED AT 250 WORDS) more...
- Published
- 1994
- Full Text
- View/download PDF
49. Functional adaptation of en bloc-transplanted pediatric kidneys into pediatric recipients.
- Author
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Bergmeijer JH, Cransberg K, Nijman JM, Molenaar JC, Wolff ED, and Provoost AP
- Subjects
- Adaptation, Physiological, Adolescent, Child, Female, Humans, Infant, Kidney anatomy & histology, Kidney diagnostic imaging, Male, Ultrasonography, Kidney physiology, Kidney Transplantation methods
- Published
- 1994
- Full Text
- View/download PDF
50. Modulation of glomerular hypertension defines susceptibility to progressive glomerular injury.
- Author
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Simons JL, Provoost AP, Anderson S, Rennke HG, Troy JL, and Brenner BM
- Subjects
- Animals, Arginine analogs & derivatives, Arginine pharmacology, Blood Pressure, Disease Susceptibility, Enalapril pharmacology, Glomerulosclerosis, Focal Segmental pathology, Glomerulosclerosis, Focal Segmental physiopathology, Hemodynamics, Hypertension, Renovascular chemically induced, Kidney Glomerulus pathology, Male, NG-Nitroarginine Methyl Ester, Nitric Oxide antagonists & inhibitors, Rats, Rats, Mutant Strains, Renal Circulation, Glomerulosclerosis, Focal Segmental etiology, Hypertension, Renovascular physiopathology, Kidney Glomerulus physiopathology
- Abstract
The fawn-hooded rat constitutes a spontaneous model for chronic renal failure with early systemic and glomerular hypertension, proteinuria (UpV) and high susceptibility to development of focal and segmental glomerular sclerosis (FGS). It has been argued that uninephrectomy (UNX) accelerates the development of glomerular injury by aggravation of glomerular hypertension and by an independent effect to promote glomerular enlargement. The present study was performed to further delineate the importance of these parameters for the development of FGS. At the age of eight weeks male rats were UNX and randomly assigned to either control (CON), enalapril (ENA) or Nw-nitro L-arginine methyl ester (NAME) treatment. In all groups glomerular hemodynamic studies were performed four weeks post-UNX. Systemic blood pressure and UpV were monitored for 4 to 12 weeks post-UNX. Kidneys were then prepared for morphologic study. ENA treatment achieved control of both systemic and glomerular hypertension, maintenance of glomerular hyperfiltration and hyperperfusion, increased ultrafiltration coefficient(Kf), and long-term protection against UpV and FGS. NAME rats showed aggravation of both systemic and glomerular hypertension, decreased renal perfusion and filtration with reduced Kf, and high filtration fraction. The incidence of FGS in NAME and CON groups was similar at 8 and 12 weeks post-UNX, respectively. Glomerular enlargement was present in CON and ENA rats, but did not correlate with injury, while glomerular tuft size was lowest in NAME rats, which displayed prominent glomerular injury. Systemic blood pressure correlated strongly with glomerular capillary pressure. We conclude that systemic and glomerular hypertension govern the development of UpV and FGS.(ABSTRACT TRUNCATED AT 250 WORDS) more...
- Published
- 1994
- Full Text
- View/download PDF
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