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Severe proteinuria is a defining factor of nephrotic syndrome irrespective of the etiology. Investigation of congenital nephrotic syndrome has shown that dysfunction of glomerular epithelial cells (podocytes) plays a crucial role in this disease. Acquired nephrotic syndrome is also assumed to be associated with podocyte injury. Here we identify an association between variants in GPC5, encoding glypican-5, and acquired nephrotic syndrome through a genome-wide association study and replication analysis (P value under a recessive model (P(rec)) = 6.0 × 10(-11), odds ratio = 2.54). We show that GPC5 is expressed in podocytes and that the risk genotype is associated with higher expression. We further show that podocyte-specific knockdown and systemic short interfering RNA injection confers resistance to podocyte injury in mouse models of nephrosis. This study identifies GPC5 as a new susceptibility gene for nephrotic syndrome and implicates GPC5 as a promising therapeutic target for reducing podocyte vulnerability in glomerular disease.

Advanced glycation end products (AGE) are significantly increased in end-stage renal disease patients and it has been suggested that AGE accumulation is related to the progression of cardiovascular disease. An autofluorescence reader non-invasively assesses AGE accumulation using skin autofluorescence under ultraviolet light. Skin autofluorescence has been reported to be an independent predictor of mortality in Caucasian hemodialysis patients. The aim of this study was to assess whether skin autofluorescence in Japanese hemodialysis patients is related to the presence of cardiovascular disease. In this cross-sectional study, patients on maintenance hemodialysis (N = 128; 59 men, 69 women) were included. AGE accumulation was assessed by skin autofluorescence using an autofluorescence reader. Associations between skin autofluorescence, cardiovascular disease, and other parameters were studied. Skin autofluorescence correlated with age (r = 0.32, P

Mesangioproliferative glomerulopathy (MesPGN) is a well-defined pathohistological entity. However, the clinical characteristics and prognosis have not been fully established in patients without immunoglobulin (Ig)A (N-IgAN) in contrast to patients with IgA nephropathy (IgAN).A total of 837 consecutive patients underwent renal biopsies. Among them, 465 patients were diagnosed with MesPGN by light microscopy. With immunofluorescent study and electron microscopy (EM), 344 were diagnosed as having IgAN. Among the rest, 84 patients who had no immunofluorescence evidence of IgA and no deposits in EM were defined as N-IgAN. We compared the clinical characteristics, histological findings, and genotypes of the angiotensin-converting enzyme (ACE) gene and plasminogen activator inhibitor-1 gene between IgAN and N-IgAN patients.Urinary protein excretion and the degree of hematuria were significantly lower in N-IgAN than IgAN patients (0.50 vs. 0.82 g/day; P = 0.01), (1.33 vs. 2.50; P0.001, respectively). Creatinine clearance was higher in N-IgAN than IgAN patients (89.4 vs. 74.4 ml/min; P0.001). Histopathologically, N-IgAN patients had significantly less advanced glomerular and tubulointerstitial lesions than IgAN patients. Pathological grades in patients with untreated IgAN were more advanced in a time-dependent manner, whereas there was no relationship between histological grades and time of illness in N-IgAN patients. Frequency of the DD genotype of the ACE gene was significantly lower in N-IgAN (DD/ID+II = 8/76) than IgAN (24/90) patients.IgA-negative MesPGN is a distinct type of glomerulopathy with a benign renal prognosis. Insertion/deletion polymorphisms of the ACE gene may play some role in the genesis and progression of MesPGN.

Abnormalities in D 1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein–coupled receptor kinase type 4 (GRK4) causes the impaired renal D 1 receptor function in hypertension. We measured renal GRK4 and D 1 and serine-phosphorylated D 1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious- uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar–Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D 1 receptors were &90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D 1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D 1 receptor control of sodium excretion and blood pressure in genetic hypertension.

The effect of selectively decreasing renal angiotensin II type 1 (AT 1 ) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT 1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT 1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT 1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT 1 receptors. AT 1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN–treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT 1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels.

Among the complications in percutaneous renal biopsy, bleeding is the most frequent and sometimes becomes fatal. We prospectively studied 394 consecutive percutaneous renal biopsies in 359 patients (male/female = 188/171). The mean age of the patients was 44.0 ± 17.2 years. Percutaneous renal biopsies were performed on native kidneys under direct visualization by ultrasound, using an automated spring-loaded biopsy device and a 16-cm 18 G needle. The most common complication was hematoma (n = 149, 37.8%). “De novo macrohematuria” was observed in 29 patients (7.4%). Other complications included pain (n = 27, 6.9%), loss of blood (n = 17, 4.3%), and renal dysfunction (increase of serum creatinine more than 0.2 mg/dl, n = 9, 2.2%). Although there were no severe complications such as loss of blood requiring a blood transfusion, loss of kidney function, or death, 10 patients had an extended rest period in bed because of moderate complications. Hypertension and amyloidosis had significant influence on the complications. For those who are clinically suspected of having amyloidosis or hypertension, more careful biopsy procedures and observations are necessary.

Background: In diabetic nephropathy (DN) small vessels are frequently observed around the glomerular vascular pole in addition to normal afferent and efferent arterioles; this is regarded as neovascularization. Because vascular endothelial growth factor (VEGF) promotes vascular generation, the authors investigated the relationship between glomerular VEGF gene expression and structural glomerular changes in the early stage of human DN. Methods: Kidney specimens were obtained from 18 type 2 DN patients by open renal biopsy. Additional vessels were distinguished by light microscopy as either afferent or efferent arterioles. Glomerular VEGF messenger RNA expression was determined by using in situ hybridization. The mesangial matrix area was quantified, and the ratio of the mesangial matrix area to the whole glomerular area was calculated to determine the mesangial matrix index (MMI). Results: There were significantly more glomeruli with extra vessels in DN than in normal kidneys. The degree of neovascularization was significantly increased in DN and correlated with the magnitude of VEGF messenger RNA expression (r2 = 0.46, P = 0.010) and MMI (r2 = 0.45, P = 0.0093). Conclusion: These findings suggest that glomerular VEGF may be involved in structural changes in human DN at an early stage.

Background and aim Corticosteroid therapy is an effective way of treatment for many renal diseases, however, it is sometimes associated with infections. Our aim is to identify useful predictive markers of infection during steroid therapy. Methods We examined 121 patients (M/F = 71/50, mean age 43.8, range 15 - 82 years) who were treated with corticosteroids (IgA nephropathy in 51, minimal-change disease in 17, membranous nephropathy in 16 rapidly progressive glomerulonephritis (RPGN) in 13, lupus nephritis in 12 and other disorders in 12). Karnofsky's performance score (KPS) was employed to assess the physical functional status at the time of diagnosis. Infections were defined as conditions that required more than 1-week care, and those that caused the patient's death. Results Nineteen patients (15.7%) had infections during treatment. A logistic multivariate analysis showed significant correlations between infection and the use of immunosuppressive agents (relative risk RR = 7.7, p = 0.0265), ages of 52.9 years or more (RR = 13.5, p = 0.0026), initial number of lymphocytes (Lym) less than 1.250/microl (RR = 14.2, p = 0.0011), and KPS less than 77.4 (RR = 12.1, p = 0.0020). All correlations with infection were independent of all the other variables listed above. Conclusion KPS, along with age, Lym and the use of immunosuppressive agents, are useful for the prediction of infectious complications during steroid therapy.

Hypertension is a major risk factor for atherosclerotic cardiovascular disease. Selectins, cell-surface adhesion molecules involved in leukocyte rolling and attachment to the vascular endothelium, play a role in the initiation of atherosclerosis. We investigated whether or not serum levels of soluble adhesion molecules are elevated in patients with essential hypertension (EH) and examined whether antihypertensive therapy lowers such levels. Twenty-one patients who had untreated mild to moderate EH without diabetes mellitus, hyperlipidemia, or obesity were recruited at a clinic for hypertensive patients. Blood pressure was measured, and the serum levels of soluble E-selectin, P-selectin, L-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular-cell adhesion molecule 1 (VCAM-1) were determined by enzyme-linked immunosorbent assays before and after 12, 24, and 53 weeks of antihypertensive treatment with benidipine, a long-acting calcium channel blocker, given at a dose of 6 mg/day for 53 weeks. As a control, 21 age- and sex-matched patients without hypertension were studied. Serum E- and P-selectin levels were significantly higher in the subjects with EH than in the controls (p0.01). There were no differences in serum levels of soluble L-selectin, VCAM-1, or ICAM-1 levels between the patients with EH and the controls. Treatment with benidipine decreased the elevated blood pressure over a 53-week study period (mean blood pressure: 119.8 +/- 6.5 mmHg at baseline, 101.0 +/- 5.9 mmHg at 12 weeks, 98.6 +/- 7.3 mmHg at 24 weeks, and 93.9 +/- 5.5 mmHg at 53 weeks). Serum levels of soluble E- and P-selectin decreased after the initiation of benidipine treatment and correlated with diastolic blood pressure. Serum levels of soluble L-selectin, VCAM-1, and ICAM-1 did not change significantly during the period of benidipine treatment. Benidipine treatment reduced the content of P-selectin in the platelets from patients with EH, as determined by Western blot analysis. In conclusion, decreased blood pressure may reduce the rate of progression of atherosclerosis by affecting the expression of E- and P-selectin in the endothelium, the platelets, or both. Benidipine may be protective against vascular damage in people with hypertension, not only by lowering blood pressure, but also by inhibiting the expression of selectins.

Diabetic nephropathy is a common complication in diabetes mellitus (DM). Thiazolidinedione (TZD) is thought to ameliorate diabetic nephropathy, however, the mechanism has not been elucidated. We hypothesized that VEGF participates in the pathogenesis of diabetic nephropathy and that TZD may be beneficial for the treatment of diabetic nephropathy through its effect on VEGF. Increased VEGF expression was demonstrated in the glomeruli of DM rats and rat mesangial cells (RMC) incubated with high medium glucose. It was also demonstrated that VEGF promoted mesangial cell proliferation, which was inhibited by TZD. It was shown that a rapid fall and rise of ambient glucose concentration induces more VEGF production and cell proliferation in RMC than in cells with continuously high glucose medium, which was also inhibited by TZD. Prostaglandin J2 and protein C kinase inhibitors significantly inhibited [3H]thymidine incorporation in RMC incubated with VEGF, which was inhibited by TZD. These findings indicate that a rapid change of glucose concentration promotes RMC proliferation by the increased production of VEGF. TZD has an inhibitory action through, at least in part, PPAR-gamma.

Background Insulin resistance has been reported to induce hypertension. Previous studies described that there was no relationship between insulin resistance and hypertension in patients with chronic renal diseases with mild to moderate renal dysfunction. The aim of the present study is to clarify the relationship between insulin resistance and blood pressure, renal function, histopathological changes and other characteristics in IgA nephropathy (IgAN). Methods Eighty-eight IgAN patients were included in this cross-sectional study. Hypertension was diagnosed according to the WHO/ISH criteria. Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR). Results Male gender, age, body mass index, serum creatinine, urinary protein excretion, triglycerides and HOMA-IR were positively correlated with hypertension. C(Cr), serum albumin and HDL cholesterol were negatively correlated with blood pressure by Spearman's simple correlation test. By logistic multivariate analysis, C(Cr), insulin resistance, age and male gender were significantly correlated with hypertension, independently of all other variables. Conclusions Insulin resistance is not directly related to renal dysfunction, but is also independently associated with hypertension in IgAN. Since hypertension is considered as a risk factor for renal disease progression, insulin resistance may be an indirect deteriorating factor for IgAN. To identify and improve insulin resistance may be another therapeutic target in the clinical management of IgAN.

Background. Thromboxane (TX) A2 inhibition or prostaglardin (PGI2) infusion prevents ischemic acute renal failure (ARF) in animal models. However, the pathophysiological roles of the prostanoid receptors in the development of ischemic ARF are not fully understood, partly because of the limited specificity of their inhibitors or antagonists. Methods. We investigated whether targeted disruption of the PGI2 receptor (IP) or TXA2 receptor (TP) genes conferred susceptibility to renal ischemic-reperfusion injury, using IP and TP knockout mice. Results. Serum creatinine concentration in TP knockout mice was not significantly different from that in wild-type controls. There were no significant histological differences between TP knockout and wild-type mice. Likewise, IP knockout mice showed no significant differences from the wild-type controls in regard to creatinine concentration or histological damage. Conclusions. Lack of TP or IP had no influence on postischemic ARF in mice, indicating that receptors for TXA2 or PGI2 may have minimal roles in the development of this mouse model of ischemic ARF.

Aims and Methods: This study was carried out to clarify whether the urinary excretion of type IV collagen (u-IV collagen) detected by specific radioimmunoassay, can be used as an indicator for the progression of diabetic nephropathy. Results: u-IV collagen was higher in diabetic subjects with microalbuminuria and overt proteinuria than those with normoalbuminuria, IgA nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, or control normal subjects. u-IV collagen was positively correlated with serum and urinary β2-microglobulin and negatively with creatinine clearance only in diabetic patients, but not in patients with other glomerular diseases. The serum type IV collagen was not different between all the groups, and not correlated with its urinary excretion. In the advanced diabetic nephropathy, immunoreactive type IV collagen was detected in glomerular basement membrane (GBM), tubular basement membrane and Bowman’s capsule much more than that in the normal kidney. Conclusion: These findings indicated increased production and degeneration of type IV collagen in diabetic nephropathy. It is suggested that augmented turnover of type IV collagen in GBM and tubular basement membrane results in increased concentrations of free u-IV collagen. Therefore, measurement of u-IV collagen may be a useful, specific indicator of the progression of diabetic nephropathy.

Abstract We have shown recently that mechanical stretch of cultured rat aortic smooth muscle cells induces a marked increase in gene expression of the vasorelaxant parathyroid hormone–related peptide. In the present study, we investigated whether mechanical force affected the in vivo parathyroid hormone–related peptide gene expression in blood vessels. Northern blot analysis revealed that stretch of isolated rat aortic strips increased the expression level of parathyroid hormone–related peptide mRNA. The parathyroid hormone–related peptide transcript level in aorta and mesenteric vessels from 18-week-old spontaneously hypertensive rats (SHR) was 2.5- and 2.2-fold higher, respectively, compared with age-matched Wistar-Kyoto (WKY) controls, whereas the parathyroid hormone–related peptide mRNA level in aorta from normotensive 4-week-old SHR was similar to that of age-matched WKY controls. The aortic parathyroid hormone–related peptide content was higher in 18-week-old SHR than in age-matched WKY controls. Moreover, treatment of mature SHR with an angiotensin II type 1 receptor antagonist or hydralazine caused a concomitant decrease in the parathyroid hormone–related peptide transcript level in aorta with lowering of blood pressure. These results suggest that the in vivo parathyroid hormone–related peptide gene expression in blood vessels is under the control of mechanical force, pointing to a role of parathyroid hormone–related peptide in the regulation of vascular tone.

Tyrosine kinase dependent expression of TGF-β induced by stretch in mesangial cells. Increased glomerular hydraulic pressure has been suggested as a major causative factor in the development of glomerular sclerosis. The elevation of glomerular pressure increases the magnitude of stretch to mesangial cells. The study was, therefore, designed to investigate the effect of mechanical stretch on expression of TGF-β and extracellular matrix components in cultured rat mesangial cells. The results showed that mechanical stretch stimulated mRNA expression for TGF-β1 and TGFβ3 in a time dependent manner, and that mesangial cells secreted substantial amounts of TGF-β proteins in response to stretch. Stretch was also shown to stimulate mRNA expression for collagen types I and IV, and fibronectin, major components of mesangial extracellular matrix. The stretch-induced mRNA expression for extracellular matrix components was inhibited by neutralizing antibody to TGF-β. Moreover, stretch-induced mRNA expression of TGF-β was inhibited by tyrosine kinase inhibitors, genistein or herbimycin A, whereas Ca channel blockers nitrendipine or Gd3+, and inhibitors for protein kinase A or C had no effect. These findings indicate that stretch induced TGF-β mRNA primarily through tyrosine kinase-dependent mechanisms in cultured rat mesangial cells, and the secreted TGF-β may play a significant role for the stretch-induced expression of extracellular matrix proteins. Our results suggest that stretch-induced TGF-β of mesangial cells might be a mediator in the progression of glomerular sclerosis as an autocrine/paracrine factor.

Background This study examined whether targeted disruption of the genes for the prostacyclin receptor (IP) or the thromboxane A2 receptor (TP) confers a susceptibility to salt-dependent hypertension. Methods and Results Eight female IP- or TP-deficient mice were examined. Baseline systolic blood pressure (SBP) did not differ between TP(-/-) and TP(+/+), but was significantly lower in the IP(-/-) group than in the IP(+/+). With a high salt diet, SBP in IP(-/-) gradually increased. In contrast, SBP in the IP(+/+), TP(-/-), or TP(+/+) groups remained unchanged. Conclusions The prostacyclin receptor may participate in the maintenance of baseline BP. With salt loading, BP adaptation may take place, at least in part, via IP mediated signals. (Circ J 2005; 69: 124 -126)

Summary: Serum hepatocyte growth factor (HGF) concentrations were measured in healthy volunteers, chronic renal failure patients without renal replacement therapy and haemodialysis patients. Serum HGF concentrations in healthy volunteers, chronic renal failure patients and haemodialysis patients were 0.18 ± 0.04 (s.d.), 0.28 ± 0.06 and 0.46 ± 0.22 ng/mL, respectively. Serum HGF concentration in chronic renal failure patients was significantly higher than that in healthy volunteers. Serum HGF concentration in haemodialysis patients was significantly higher than those in healthy volunteers and chronic renal failure patients. There was no regression of serum HGF concentration on age, sex, history of haemodialysis, prehaemodialysis serum creatinine concentration, and serum tumour necrosis factor (TNF)-α concentration. We conclude that chronic renal disease and haemodialysis therapy are contributing factors to an increased serum HGF concentration.

In summary, we have shown that adenovirus vector efficiently introduced foreign gene into cultured renal cells both of mesangial and tubular origin. Genes transferred were properly expressed to produce the molecules of expected function. It was possible to introduce the gene into nearly 100% of the cells treated. Expression of the gene began as early as 12 hours after the infection, increased until 48 hours and persisted at least up to eight days. Finally, the vector was non-toxic to the cells, as judged from simple toxicity tests. Successful application of adenovirus vector enables for us to study function of pertinent molecules in suitable host cells and opens a new way for examining renal cellular physiology and pathophysiology.

Co-regulated expression of glomerular 12/15-lipoxygenase and interleukin-4 mRNAs in rat nephrotoxic nephritis. Arachidonate 12- and 15-lipoxygenase (LO) products are generated in experimental glomerulonephritis. 15-S-HETE (a 15-LO product) and lipoxins (interaction products between 5-LO and either 12-LO or 15-LO) counteract the proinflammatory actions of leukotrienes. IL-4 has been shown to up-regulate 15-LO gene expression in human leukocytes. Based on homology with human 15-LO, we cloned a 0.76 kbp fragment of a rat LO cDNA from leukocytes stimulated by interleukin-4 (IL-4). The deduced amino acid sequence shows 71.0% and 60.1% homology to human 15-LO and 12-LO, respectively, and 100% homology to a recently cloned “leukocyte type” rat 12-lipoxygenase enzyme, which possesses significant 15-lipoxygenase activity (heretofore referred to as “12/15-LO”). A deletion mutant was utilized to generate internal standard cRNA in quantitative PCR assays. Glomerular 12/15-LO mRNA increased significantly over controls 24 and 48 hours after NTS injection, then decreased at 72 hours. RNA from NTS glomeruli contained higher levels of 12/15-LO mRNA than that from unstimulated peripheral leukocytes, suggesting that 12/15-LO transcription is up-regulated locally in native and/or infiltrating glomerular cells. Glomerular IL-4 mRNA increased markedly 16 hours post-NTS, and was then reduced, suggesting a potential role for T cell-derived IL-4 in directing the expression of 12/15-LO during glomerulonephritis. This represents the first demonstration of tandem regulated in vivo gene expression for a lymphokine (IL-4) and a lipoxygenase, both of which promote counter-inflammatory influences in immune complex-mediated injury.

This study was designed to examine the potential effect(s) of dietary supplementation with L-arginine on the renal microcirculation of female Munich-Wistar rats with ablation of 60 to 70% of total renal mass. All rats were fed a standard rat chow containing 22.8% protein (1.42% L-arginine). Groups 1 (N = 6) and 3 (N = 7) drank tap water and had micropuncture studies after 5 to 6 or 15 to 16 wk, respectively, of subtotal renal ablation. Groups 2 (N = 5) and 4 (N = 7) drank tap water supplemented with L-arginine (1%) and had micropuncture studies after 5 to 6 or 15 to 16 wk, respectively, of subtotal renal ablation. Glomerular micropuncture studies revealed no differences in any of the parameters of glomerular hemodynamics measured 5 to 6 wk after renal ablation (Groups 1 versus 2). However, by 15 to 16 wk postnephrectomy, values of glomerular capillary pressure and efferent arteriolar resistance were significantly greater and the glomerular capillary ultrafiltration coefficient was significantly lower in rats drinking tap water than in rats drinking tap water supplemented with L-arginine. Single-nephron GFR, single-nephron plasma flow rate, and afferent arteriolar resistance were not different between these two groups. The data suggest that the long-term administration of L-arginine prevents the progression of glomerular sclerosis in rats with subtotal nephrectomy, at least in part, by ameliorating glomerular capillary hypertension.

Glomerular hypertension aggravates glomerular sclerosis by inducing growth factors, e.g., transforming growth factor-β (TGF-β) to mesangial matrix expansion. Smads are intracellular proteins that transmit signals from TGF-β to nucleus, and Smads are also negatively regulated by inhibitory Smads (I-Smads), Smad6 and Smad7. However, little is known about the role of I-Smads in glomerular hypertension. We studied I-Smad expression in cultured mesangial cells subjected to mechanical stretch as an in vitro model of glomerular hypertension.Rat mesangial cells were cultured under cyclic mechanical stretch conditions using the Flexercell Strain Unit. Phosphorylated Smad1 and Smad2 were determined by Western blots. The expression of Smad6 and Smad7 mRNAs was determined by Northern blots. Stretch-mediated I-Smad mRNAs of cells pre-treated with MAPK-ERK kinase inhibitor, U0126, were also determined. Localization of phospho-Smad1, Smad6 and Smad7 proteins in the glomerulus of Dahl salt-sensitive rats was determined by immunohistochemistry.Stretch stress increased phospho-Smad1 levels, and significantly decreased Smad6 mRNA to 32 % of control, and increased Smad7 mRNA to 136 % of control. U0126 significantly attenuated stretch-mediated decreases in Smad6 mRNA, but had no effect on stretch-mediated increases in Smad7 mRNA. Phospho-Smad1, Smad6 and Smad7 proteins were localized in podocytes and mesangial cells of Dahl rats.Mechanical stretch increases phospho-Smad1 levels and down-regulates Smad6 mRNA expression in mesangial cells. Stretch-mediated down-regulation of Smad6 is partially involved in ERK1/2 activation. These results indicate that glomerular hypertension might augment Smad1 signaling with concomitant attenuation of Smad6-mediated negative feedback.

We assessed the role of leukotrienes (LTs) in Munich-Wistar rats with passive Heymann nephritis (PHN), an animal model of human membranous nephropathy. 10 d after injection of anti-Fx1A antibody, urinary protein excretion rate (Upr) in PHN was significantly higher than that of control. Micropuncture studies demonstrated reduced single nephron plasma flow and glomerular filtration rates, increased transcapillary hydraulic pressure difference, pre- and postglomerular resistances, and decreased ultrafiltration coefficient in PHN rats. Glomerular LTB4 generation from PHN rats was increased. Administration of the 5-LO activating protein inhibitor MK886 for 10 d markedly blunted proteinuria and normalized glomerular hemodynamic abnormalities in PHN rats. An LTD4 receptor antagonist SK&F 104353 led to an immediate reduction in Upr and to reversal of glomerular hemodynamic impairment. Ia(+) cells/glomerulus were increased in PHN rats. In x-irradiated PHN rats, which developed glomerular macrophage depletion, augmented glomerular LT synthesis was abolished. Thus, in the autologous phase of PHN, LTD4 mediates glomerular hemodynamic abnormalities and a hemodynamic component of the accompanying proteinuria. The synthesis of LTD4 likely occurs directly from macrophages or from macrophage-derived LTA4, through LTC4 synthase in glomerular cells.

We examined the actions of intravenously administered manidipine on systemic and renal microcirculatory hemodynamics and its efficacy in antagonizing endothelin-1 (ET-1)-evoked responses. Manidipine was a potent vasodilator with preferential activity in the renal vasculature. Its administration in optimal doses resulted in decreases in systemic arterial pressures accompanied by increases in renal perfusion and filtration rates. Its primary sites of action in the kidney were at both pre- and postglomerular arteriolar sites. Manidipine was capable of near-total reversal of the sustained elevations in arterial pressure and the progressive reductions in renal blood flow and glomerular filtration rates induced by intravenously administered ET-1. In the presence of prolonged calcium channel blockade, subsequent administration of ET-1 led to paradoxic hypotensive responses, which could be profound and blocked by an inhibitor of nitric oxide synthesis. These unexpected vasorelaxant actions of ET-1 in the presence of manidipine were likely caused by the dual effects of antagonism of its own intrinsic vasoconstrictor action (through calcium channel blockade), as well as ET-1-evoked release of the endothelium-derived relaxing factor, nitric oxide.

On the two 13Cr-Fe alloys including 0.8%Si and 2.5%Al which were given attention as a new magnetic alloy for alternating field, the amplitude relative permeability in magnetic field is measured and studied to influence of thickness at ring specimen and electrical resistivity as compared with magnetic soft iron and 1%Si-Fe alloy. The amplitude relative permeability of 0.8Si-13Cr-Fe alloy is superior than those of magnetic soft iron and 1%Si-Fe alloy at ferquency range 5 to 20kHz and that of 2.5Al-13Cr-Fe alloy is higher than the compared alloys at almost all frequencies invesigated, although the FeCr alloys have lower magnetic properties in direct magnetic field. Smaller dependence of amplitude relative permeability in alternating field on the thickness of specimens is observed for the two FeCr magnetic alloys than magnetic soft iron and 1%Si-Fe alloy. These changes are dependent on their electrical resistivity.

A 42-year-old man previously diagnosed with congenital diabetes insipidus (DI) developed polydipsia and polyuria (water intake and urine excretion, above 20 l per day). On admission, a serum sodium level of 124 mEq/l, a serum chloride level of 87 mEq/l, and plasma osmolality of 254 mOsm/kg H2O were found, although urine osmolality was always less than 100 mOsm/kg H2O, with daily urine excretion of more than 15 l. Creatinine clearance was 153 l/day. Initially, he had free access to water and his daily water intake was 20–27 l. Restriction of water intake (10 l/day) normalized his serum sodium levels and alleviated his general fatigue. Hyponatremia is a rare fluid electrolyte disturbance in DI. We found no reports of hyponatremia associated with congenital nephrogenic DI, presumably because the osmosensing mechanism is intact in such patients. The use of thiazides for the treatment of polyuria, in combination with potassium-sparing diuretics and salt restriction, may accelerate the genesis of hyponatremia caused by psychogenic polydipsia in nephrogenic DI.

Advanced glycation end products (AGE) are significantly increased in end-stage renal disease patients and it has been suggested that AGE accumulation is related to the progression of cardiovascular disease. An autofluorescence reader non-invasively assesses AGE accumulation using skin autofluorescence under ultraviolet light. Skin autofluorescence has been reported to be an independent predictor of mortality in Caucasian hemodialysis patients. The aim of this study was to assess whether skin autofluorescence in Japanese hemodialysis patients is related to the presence of cardiovascular disease. In this cross-sectional study, patients on maintenance hemodialysis (N = 128; 59 men, 69 women) were included. AGE accumulation was assessed by skin autofluorescence using an autofluorescence reader. Associations between skin autofluorescence, cardiovascular disease, and other parameters were studied. Skin autofluorescence correlated with age (r = 0.32, P0.01), diabetes (r = 0.21, P = 0.02), carotid intima-media thickness (IMT) (r = 0.23, P = 0.02), high-sensitivity C-reactive protein (hsCRP) (r = 0.20, P = 0.03), and plasma pentosidine (r = 0.20, P = 0.03). Each parameter was compared in patients with and without cardiovascular disease; the gender distribution, age, carotid IMT, high-density lipoprotein cholesterol, hsCRP, and skin autofluorescence were significantly related to the presence of cardiovascular disease. Multiple logistic regression analysis identified carotid IMT (OR 6.76), hsCRP (OR 1.41), and skin autofluorescence (OR 2.29) as significant factors for the presence of cardiovascular disease. Increased skin autofluorescence was related to the presence of cardiovascular disease in Asian (non-Caucasian) hemodialysis patients, and therefore an autofluorescence reader might have the potential to be a useful assessment of cardiovascular risk in these patients.

Background. Tissue accumulation of advanced glycation end-products (AGE) is thought to be a contributing factor to the progression of cardiovascular disease (CVD). Skin autofluorescence, a non-invasive measure of AGE accumulation using autofluorescence of the skin under ultraviolet light, has shown associations with CVD in haemodialysis patients. The present study aimed to evaluate relationships of skin autofluorescence to renal function aswell as CVD in pre-dialysis patients with chronic kidney disease (CKD). Methods. Subjects in this cross-sectional analysis comprised 304 pre-dialysis CKD patients [median age, 62.0 years; median estimated glomerular filtration rate (eGFR), 54.3 mL/min/1.73 m 2 ; diabetes, n=81 (26.6%)]. AGE accumulation in skin was assessed by skin autofluorescence using an autofluorescence reader. Relationships between skin autofluorescence, eGFR, CVD history and other parameters were evaluated. Results. Skin autofluorescence correlated negatively with eGFR (r = −0.42, P

Background/Aims: The beneficial effects of omega-3 polyunsaturated fatty acids (n–3 PUFA) in the treatment of immunoglobulin A nephropathy (IgAN) have been reported. Perilla frutescens (Linn.) Britton var. frutescens is grown in Eastern Asia and its seed (perilla seed) is rich in α-linolenic acid, an n–3 PUFA. We investigated the antinephritic effects of perilla seed oil in a mouse model of IgAN. Methods: Ten-week-old high IgA ddY mice were fed diets containing either perilla seed oil (PS group) or corn oil (C group, control). After 20 weeks, we compared body weight, blood pressure, serum creatinine levels, IgA levels, fatty acid composition, urinary protein excretion, mesangial matrix expansion, and glomerular transforming growth factor-β1 mRNA expression between groups. Results: Serum n–3 PUFA levels were higher in the PS group than the C group (p < 0.001). Blood urea nitrogen levels were lower (p = 0.0246) and urinary protein excretion was reduced (p = 0.0198) in the PS group. Mesangial matrix expansion (p = 0.0063) and glomerular transforming growth factor-β1 mRNA expression (p = 0.0291) were suppressed in the PS group. No significant differences between groups were found in body weight, blood pressure, serum IgA, and creatinine levels. Conclusions: Dietary perilla seed oil supplement could suppress the progression of IgAN.

門脈本幹の遮断による肝内血行動態の変化を明らかにするために,脾皮下固着ラットを用いて,門脈遮断後,経時的に門脈終末枝圧と中心静脈圧との変化をmicropuncture法によって測定し,肝組織血流量および求肝性副血行路の形成状態との関連癒検討した.門脈結紮により,門脈終末枝圧,門脈終末枝-中心静脈圧較差,肝組織血流量は低下したが,門脈終末枝圧,圧較差は結紮後4週で,肝組織血流量は同じく3日で対照値に復した.門脈造影では,門脈結紮1週後より求肝性副血行路の形成を認め,4週後で著明となり肝内門脈枝も明瞭に造影された.門脈終末枝圧,門脈終末枝-中心静脈圧較差の回復は求肝性副血行路形成の経過とよく相関したことから,結紮後早期に代償性の肝動脈血流量増加があり,4週では求肝性副血行路形成によって門脈血流量が回復するものと推測された.

BACKGROUND: The plasminogen activator inhibitor-1 (PAI-1) 4G/4G genotype influences the development of diabetic nephropathy and lupus nephritis. However, the association of the PAI-1 4G/4G genotype and IgA nephropathy (IgAN) has not been investigated. SUBJECTS AND METHODS: The PAI-1 and ACE polymorphisms were examined in 270 healthy volunteers and 202 biopsy-proven IgAN patients, including 117 untreated IgAN patients who had an annual health check, allowing an estimation of the time of onset of overt proteinuria and/or hematuria. The relationship between the gene polymorphisms and the pathogenesis of IgAN were examined in 202 IgAN patients and the relationship between the gene polymorphisms clinical and pathohistological findings were examined in 117 untreated IgAN patients cross-sectionally at the time of renal biopsy. RESULTS: 202 IgAN patients and 117 untreated IgAN patients did not have different frequencies in PAI-1 4G/5G (4G/4G : 4G/5 : 5G/5G = 82 : 90: 30, 45 : 55 : 17) and ACE I/D (DD : ID : II = 41 : 82 : 79, 21 : 54 : 42) gene polymorphisms compared with 270 healthy volunteers (4G/4G : 4G/5 : 5G/5G = 99 : 124 : 47, DD : ID : II = 53 : 106 : 111). However, IgAN with 4G/4G had significantly more advanced histological changes than IgAN with 4G/5G or 5G/5G both in glomerular and tubulointerstitial findings (p < 0.0005). The disease duration in IgAN with 4G/4G was shorter than in IgAN with 4G/5G + 5G/5G (6.22 +/- 6.38 and 8.80 +/- 9.79 years, respectively, p < 0.05). Creatinine clearance (Ccr) in IgAN with 4G/4G was significantly lower than IgAN with 4G/5G or 5G/5G (72.3 +/- 26.5 and 82.4 +/- 22.8 ml/min, respectively, p < 0.05). The mean urinary protein excretion in IgAN with 4G/4G was significantly more than in IgAN with 4G/5G or 5G/5G (1.10 +/- 1.48 and 0.70 +/- 1.01 g/day, respectively, p < 0.05). There was no difference between IgAN with the DD ACE genotype and IgAN with ID + II genotypes in either the clinical or histopathological findings. CONCLUSION: PAI-1 polymorphism is not associated with genesis of IgA nephropathy, but may be a risk factor for the progression of IgA nephropathy in Japanese.

A 59-year-old woman with chronic renal failure due to type 2 diabetes mellitus (DM) is presented. Her father and a brother had a history of brain tumor. Her blood urea nitrogen and serum creatinine levels were 102 mg/dl and 4.5 mg/dl, respectively. Her serum Ca(2+) and Pi were within the normal range (9.4 mg/dl and 5.4 mg/dl, respectively). Her intact parathyroid hormone (PTH) level was 1 730 000 pg/ml. A (99m)Tc-methoxy-isobutylisonitrile scintigraphy showed high uptake in three parathyroid glands. A magnetic resonance image showed microadenoma in the pituitary gland. The serum gastrin level was high. Genetic examination revealed a mutation of the MEN1 gene (894-9 G --A). From these findings, she was diagnosed with multiple endocrine neoplasia (MEN) type 1. Subsequently, a parathyroidectomy was performed successfully, a parathyroid gland was transplanted to her right forearm, and her serum Ca(2+) level was controlled at 8.5-9.0 mg/dl. It is very important to identify MEN1 if an end-stage renal disease (ESRD) patient has hyperparathyroidism with multigland involvement. Examination of the MEN1 gene may be valuable to make an accurate diagnosis and choose the appropriate therapy in some ESRD patients with hyperparathyroidism.

Background. Steroid therapy for IgA nephropathy (IgAN) has been reported to ameliorate the longterm prognosis of IgAN, but its mode of action has not been fully elucidated. In this study, we examined the effect of steroids on glomerular morphological changes in IgAN. Methods. We examined 16 patients with biopsy-proven IgAN (maleufemale s11u5, mean age 32.1 years) who were divided into prognosis groups according to criteria set by the Japanese Society of Nephrology. Initially, they received a loading dose of steroids, followed by a daily dose of 10–15 mg prednisolone. After 12 months, they underwent a second biopsy, and their histological and clinical features were examined. Results. Before and after therapy, systolic blood pressure, diastolic blood pressure, serum creatinine and creatinine clearance all remained unchanged. However, urinary protein excretion decreased dramatically, from 1.6"1.7 to 0.4"0.2 guday (P-0.005). Furthermore, computerized imaging revealed a significant reduction of the mesangial matrix index (MMI) from 14.5"5.2 to 9.5"3.6% (P-0.001). The numbers of sclerosing glomeruli did not change. Conclusions. Steroid therapy reduces mesangial matrix accumulation and reduces urinary protein excretion in advanced IgAN.

We describe a 25-year-old man with Fabry disease who remained undiagnosed until progressive renal involvement had begun, because of few clinical signs or symptoms except intermittent acroparesthesia. He had non-nephrotic proteinuria and normal renal function. Renal biopsy revealed focal and segmental glomerular sclerosis with vacuolated podocytes. Electron microscopy demonstrated characteristic lamellated bodies. α-Galactosidase A (α-galA) activity was markedly decreased. Early diagnosis of Fabry disease is becoming important because of the prospect of recombinant α-galA replacement therapy. Careful history taking, physical examinations, and renal histology with electron microscopy are essential for the diagnosis in the course of the disease.(Internal Medicine 41: 983-985, 2002)

Background/Aims: IgA nephropathy (IgAN) is one of the major causes for chronic renal failure (CRF). Presence of massive proteinuria, hypertension, increased serum creatinine level and sclerotic histopathological changes of the glomerulus are known to be determinants for the progression of CRF. However, the relationships between duration of proteinuria/hematuria and histopathological changes, which may be correlated with the renal prognosis, have not been clarified. Methods: A cross-sectional, univariate analysis of clinical parameters on the four glomerular and three tubulointerstitial histopathological grades in 57 untreated biopsy-proven IgAN patients (M/F = 32/25) was performed. Results: The age at the time of renal biopsy (35.2 ± 13.0 years; mean ± SD), average duration of proteinuria (5.3 ± 5.8 years), mean urinary protein excretion (0.99 ± 1.22 g/day), serum creatinine (Cr 0.97 ± 0.28 mg/dl), Cr clearance (Ccr 75.5 ± 29.4 ml/min), and blood urea nitrogen (BUN 15.4 ± 3.9 mg/dl) were well correlated with both histopathological grades. The product of duration (years) and urinary protein excretion (g/day) at the time of renal biopsy was more significantly correlated with glomerular and tubulointerstitial histopathological grades and serum Cr. Conclusion: The natural course of IgAN is steadily progressive depending on the duration and amount of proteinuria. The product of these two factors (proteinuria index) may be a useful predictor for glomerular and interstitial histopathological changes and the fate of renal function in IgAN.

Vascular hypertrophy, which is characterized by proliferation of vascular smooth muscle cells (VSMC) and accumulation of extracellular matrix (ECM), is a major pathological change in blood vessels after chronic exposure to hypertension. Blood pressure is transmitted to the arterial walls and counterbalanced by mechanical stress, leading to stretching of circumferentially oriented VSMC, which may play some role in the pathogenesis of vascular hypertrophy. The present study was designed, therefore, to investigate the effect of mechanical stretch on the expression of ECM components and transforming growth factor-beta (TGF-beta), a potent stimulator for ECM production, and to examine the signal transduction mechanisms of the induction of TGF-beta in cultured rat VSMC. VSMC were subjected to cyclic stretch to provide a maximal elongation of 20% at a rate of 60 cycles per minute for up to 24 h. Mechanical stretch stimulated TGF-beta1 mRNA expression in a time- and elongation-dependent manner. Indeed, the secretion of TGF-beta proteins into the culture media was increased after stretch. Stretch also stimulated mRNA expression of the ECM components, type I and type IV collagen, and fibronectin, which was largely inhibited by addition of neutralizing antibody against TGF-beta. The tyrosine kinase inhibitors genistein and herbimycin A blocked the induction of TGF-beta1 and type I collagen by stretch, while protein kinase C inhibitors, the calcium channel blockers nitrendipine and gadolinium, or Ca removal from the media had no effect. These results suggest that stretch-induced, tyrosine kinase-mediated autocrine/paracrine production of TGF-8 may play a critical role in the progression of vascular remodeling associated with high blood pressure.

Modulation of renal hemodynamics by IGF-1 is absent in spontaneously hypertensive rats. We recently reported that attenuation of vasoactive agent-induced calcium signal and cell contraction of mesangial cell by insulin-like growth factor 1 (IGF-1), observed in normal mesangial cells, is totally abolished in spontaneously hypertensive rat (SHR) mesangial cells. This phenomenon might be related to the well-known aberrant regulation of SHR glomerular hemodynamics. Since it has been reported that in vivo IGF-1 infusion increases renal plasma flow (RPF) and glomerular filtration rate (GFR), we examined whether the modulation of renal function by IGF-1 is altered in SHR. We performed in vivo renal clearance studies using eight-week-old SHR and control Wistar Kyoto rats (WKY) before and after IGF-1 (5 µ g/kg) infusion into the left renal artery for 20 minutes. Mean arterial pressure was not affected by IGF-1 in both WKY and SHR. In WKY, IGF-1 increased GFR and RPF, and decreased renal vascular resistance (RVR). However, GFR, RPF, and RVR were not altered by IGF-1 in SHR, while systemic infusion of angiotensin II antagonist, CV-11974, increased GFR and RPF. The present data show that the modulation of renal hemodynamics by IGF-1 is absent in SHR. This might be related the pathophysiology of the development of hypertension.

Repetitive cyclic stretch (60 cycles/min) of rat aortic smooth muscle cells dramatically enhances the effect of angiotensin II (AII) on mRNA expression of the vasorelaxant, parathyroid hormone-related peptide (PTHrP). Thus, combined stimulation of rat aortic smooth muscle cells by cyclic stretch and low concentrations of AII, but not either alone, induces a synergistic, marked increase in the PTHrP mRNA level, in a manner dependent on the strength of stretch. This response is accompanied by a synergistic increase in secretion of PTHrP from smooth muscle cells. Removal of extracellular Ca2+ or addition of Ca2+ channel blockers, including Gd3+ and nitrendipine, does not considerably reduce the combined effects of stretch and AII, indicating that this response is not dependent on stretch-induced Ca2+ influx across the plasma membrane. The combined effect of stretch and AII on PTHrP mRNA expression is strongly attenuated by the protein kinase C (PKC) inhibitor staurosporine or by down-regulation of PKC, suggesting that PKC plays an important role in the synergistic response. However, stretch neither elicits activation of phospholipase C or PKC by itself, nor does it enhance AII-induced activation of these enzymes. These results indicate that in vascular smooth muscle cells mechanical stretch acts together with the vasoconstrictor AII to regulate the expression of the vasodilator PTHrP and suggest the role of PTHrP as a local modulator of myogenic tone.

Interactions between either the arachidonate 5-lipoxygenase (5-LO) and 15-LO or 5-LO and 12-LO can lead to the formation of lipoxins. Although the functional significance of lipoxygenase products of arachidonic acid has been recognized increasingly in glomerular inflammation, less is known regarding the specific effects of lipoxins on renal hemodynamics. Here, we examine the renal actions of lipoxin (LX) A4, LXB4, and, the recently identified 7-cis-11-trans-LXA4, which were administered into the renal artery of the euvolemic male Munich-Wistar rat. LXA4 caused increases in renal plasma flow (RPF) and glomerular filtration rate (GFR) in a dose-dependent manner. These effects were reversed during cyclooxygenase inhibition. LXB4 decreased both RPF and GFR, and its mode of action was independent of cyclooxygenase activity. 7-cis-11-trans-LXA4 decreased RPF and GFR, which effects were abolished during systemic infusion of the leukotriene D4 receptor antagonist SKF 104353. Results indicate that each of these lipoxins displays distinct hemodynamic effects via a specific mode of action on the renal vasculature of rats. Moreover, they suggest mechanisms whereby lipoxins may participate in the changes of renal hemodynamics that occur during glomerular inflammatory processes.

Porcine epidemic diarrhea virus (PEDV) was isolated in Vero cell cultures from the small intestine of a piglet experimentally infected with porcine coronavirus 83P-5, that had been isolated during outbreaks of porcine acute diarrhea and passaged in piglets. The isolation of the PEDV was successful only in Vero cells maintained in the maintenance medium (MM) containing trypsin. Infected Vero cell cultures exhibited CPE characterized by cell-fusion and syncytial formation, as well as cytoplasmic fluorescence when examined by the indirect immunofluorescent test using rabbit anti-83P-5 virus serum. The isolate was adapted to serial propagation in Vero cell cultures by adding trypsin to MM. Vero cell-adapted PEDV was successfully propagated in the MA104, CPK and ESK cell lines in the presence of trypsin in MM. Vero cell-adapted PEDV had morphologic and physicochemical characteristics similar to those of other members of the coronaviridae. The isolate differed serologically from porcine transmissible gastroenteritis (TGE) and porcine hemagglutinating encephalomyelitis viruses, and no antigenic relationship between the isolate and TGE virus could be detected by the indirect immunofluorescent test. Attempts to isolate PEDV in 6 types of primary fetal pig cell cultures and 6 of 10 established cell lines resulted in the failure, probably because these cells were damaged by the action of trypsin.

Renal glomerular and cortical metabolism of endogenous arachidonic acid by cytochrome P-450 epoxygenase yields 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EET). Using gas chromatography-mass spectrometry, we measured the synthesis of 8,9-EET from an endogenous pool of arachidonic acid in normal rat kidney. The (8S,9R) isomer was favored over the (8R,9S) isomer in a ratio (%) of 59 to 41 in isolated glomeruli and 68 to 32 in cortex tissue. (8S,9R)- but not (8R,9S)-EET elicited dose-dependent vasoconstriction on intrarenal administration in the euvolemic Munich-Wistar rat. Micropuncture measurements of glomerular dynamics revealed that (8S,9R)-EET increased afferent arteriolar resistance (RA) leading to reductions in single-nephron plasma flow rate (QA), net transcapillary hydraulic pressure difference (delta P), and consequently single-nephron glomerular filtration rate (SNGFR). There was no significant change in the value of the glomerular capillary ultrafiltration coefficient (Kf). In the presence of a cyclooxygenase inhibitor, indomethacin, the effects of 8,9-EET were reversed. RA fell leading to increases in QA and delta P, with resultant augmentation of SNGFR. Under these conditions, a modest reduction if Kf was noted. Thus (8S,9R)-EET is a stereoselective renal vasoconstrictor, preferentially generated over its optical isomer, (8R,9S)-EET, suggesting that it is biologically relevant and implying specific structural requirements for EET receptor activation. The principal mechanism of action of 8,9-EET is preglomerular vasoconstriction. The vasoconstrictor effect of 8,9-EET is CO dependent.

In the present study, we tested the direct effects of endothelin (ET) on rat kidney in vivo. ET was infused into the left renal artery of anesthetized rats at a rate of 0.5, 5, 20, or 40 pmol/h. ET reduced ipsilateral urine volume (V), clearance of inulin (CIN), and clearance of p-aminohippuric acid (CPAH) in a dose-dependent manner. Thus ET at 20 pmol/h did not change V but decreased renal plasma flow (RPF) and glomerular filtration rate (GFR) by 27.6 +/- 14.3 and 30.8 +/- 10.4%, respectively, in the ipsilateral kidney. ET at 0.5 pmol/h was without effect and at 5 pmol/h had only minor effects on CIN and CPAH of ipsilateral kidney. At 40 pmol/h, ET reduced ipsilateral V, GFR, and RPF by 52.3 +/- 21.4, 58.4 +/- 14.5, and 72.5 +/- 10.6%, respectively. Filtration fraction and fractional excretion of Na remained unchanged during ET infusion. ET, 40 pmol/h, infused into the renal artery together with atrial natriuretic peptide (ANP) at a rate of 12 pmol/h reduced the ipsilateral V, GFR, and RPF by 33.2 +/- 6.3, 26.1 +/- 6.0, and 27.2 +/- 7.1%, respectively, decrements less than those with ET alone. When a calcium-channel blocker nicardipine was infused at a rate of 2.5 micrograms/h into the renal artery together with ET, 20 pmol/h, there was little change in the ipsilateral V, RPF, and GFR; ET, 40 pmol/h, with nicardipine did not change V and decreased GFR and RPF by 25.9 +/- 5.6 and 23.1 +/- 10.8%, respectively, decrements less than those without nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)

The functional importance of the vascular endothelium in the regulation of local vascular smooth muscle and organ blood flow is now well-established. Since the discovery of endothelial-derived relaxing factor (EDRF) (1), a variety of biochemical and mechanical stimuli have been shown to induce the release of endothlial-derived relaxing or contracting factors. It seems likely that EDRF is nitric oxide (2) and it now appears that endothelial-derived contracting factor (EDCF) is primarily the peptides in the endothelin family (3–5).

To the Editor: Anorexia nervosa is sometimes accompanied by self-induced vomiting. Associated electrolyte disturbances such as metabolic alkalosis and hypokalemia1,2 may predispose patients to arrhythmias and can be difficult to treat. A 32-year-old woman with a four-year history of self-induced vomiting was hospitalized with weight loss and hypokalemia. She had received a diagnosis of anorexia nervosa three years earlier and had undergone psychotherapy. Her medications included diazepam and etizolam. At the time of diagnosis, her serum potassium level was 2.6 mmol per liter; she had been treated with oral potassium chloride supplements and triamterene. On admission to the hospital, . . .