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The Dahl/Rapp salt-sensitive (S) rat is a model of salt-sensitive hypertension and hypertensive renal disease. This study explored the role of vascular remodeling in the development of renal failure in S rats. Groups of S and Sprague-Dawley rats were given 0.3 and 8.0% NaCl diets for up to 21 days and evidence of smooth muscle proliferation identified using immunohistochemistry that showed nuclear accumulation of proliferating cell nuclear antigen and 5-bromo-2'-deoxy-uridine. Compared with the other three groups, S rats on 8.0% NaCl diet showed increased nuclear labeling of cells of the aorta and arteries and arterioles of the kidney by the end of the first week of study. Progressive luminal narrowing of the interlobular arteries and preglomerular arterioles occurred in S rats over the 3 wk on the 8.0% NaCl diet. Accumulation of pimonidazole adducts and nuclear accumulation of hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) were used as markers of tissue hypoxia. By the end of the second week of study, pimonidazole levels increased in S rats on 8.0% NaCl diet and deposition was apparent in tubular cells in the cortex and medulla. At the completion of the experiment, HIF-1[alpha] levels were increased in nuclear extracts from the cortex and medulla of S rats on this diet, compared with the other three groups of rats. The data demonstrated a disorder of the vascular remodeling process with proliferation of vascular smooth muscle cells temporally followed by development of tissue hypoxia in the hypertensive nephropathy of S rats on 8.0% NaCl diet. salt-sensitive hypertension; kidney disease; hypoxia; hypoxia-inducible factor-1; pimonidazole

Ying, Wei-Zhong, and Paul W. Sanders. The interrelationship between TGF-[[beta].sub.1] and nitric oxide is altered in saltsensitive hypertension. Am J Physiol Renal Physiol 285: F902-F908, 2003. First published July 15, 2003; 10.1152/ ajprenal.00177.2003.-The study of salt-sensitive hypertension has been facilitated by development of genetic models, especially the Dahl/Rapp salt-sensitive (S) rat. S rats rapidly become hypertensive after initiation of a diet containing 8.0% NaCl and subsequently develop arteriolonephrosclerosis and renal failure, whereas the salt-resistant (R) strain remains normotensive on the same diet. The purpose of the present study was to use these strains to demonstrate the interactions between transforming growth factor-[[beta].sub.1] (TGF-[[beta].sub.1]) and nitric oxide (NO). Young, male S and R rats were fed for 4 days diets that contained either 0.3 or 8.0% NaC1. An increase in dietary salt increased kinase activities of both p38 MAPK and p42/44 MAPK in cytoplasmic extracts from aortic rings and isolated glomeruli from both strains. Inhibition of either pathway with PD-098059 or SB-203580 decreased production of TGF-[[beta].sub.1] and nitrate plus nitrite (NOx). In both strains, production of active TGF-[[beta].sub.1] and N[O.sub.x] linearly correlated. Incubation of aortic rings and isolated glomeruli with the NO donor NOR3 decreased TGF-[[beta].sub.1] levels, whereas the NO synthase inhibitor [N.sup.[omega]]-nitro-a-arginine methyl ester increased production. The inhibitory effect of NO on production of TGF-[[beta].sub.1] was reduced in preparations from S rats. Although a close interrelationship existed between TGF-[[beta].sub.1] and NO in both strains, production of TGF-[[beta].sub.1] was increased in prehypertensive S rats and was further exaggerated with the. increase in dietary salt intake. Augmented vascular and glomerular production of TGF-[beta].sub.1] and diminished NO may contribute to the development of hypertensive nephrosclerosis in S rats. dietary salt; transforming growth factor-[[beta].sub.1]; salt sensitivity; Dahl/Rapp rat

The effects of a high-salt diet on the expression of nitric oxide synthase (NOS3) and elaboration of nitric oxide (NO) in rat kidney glomeruli are investigated by monitoring the level of NOS3 mRNA expression and calcium-dependent NO production. Results reveal that a high salt load increases the elaboration of NOS3 mRNA and enhances NO production. This effect is mediated by transforming growth factor-beta1.

Transforming growth factors (TGF) affect renal function and promote glomerulosclerosis. The mechanism of dietary salt modulation of the synthesis and secretion of TGF-beta in the rat kidney is investigated by monitoring the renal excretion of TGF-beta1 in the presence of an elevated salt diet. Results reveal that the enhancement of TGF synthesis brought about by dietary salt is mediated via a potassium channel sensitive to tetraethylammonium.

Primary cultures of rat mesangial cells were exposed to glomerulopathic light chain produced alterations in Ca2+ homeostasis to determine the effects of immunoglobulins on the mechanisms cellular homeostasis. Pretreatment of primary cultures of rat mesangial cells with glumerulopathic light chain reduced calcium transients in response to surface receptor agonists. Furthermore, the effects of monoclonal light chains on intracellular calcium homeostasis involved the inhibition of calcium influx and calcium release from intracellular stores.

Renal autoregulation is critical in maintaining stable renal blood flow (RBF) and glomerular filtration rate (GFR). Renal ischemia-reperfusion (IR)-induced kidney injury is characterized by reduced RBF and GFR. The mechanisms contributing to renal microvascular dysfunction in IR have not been fully determined. We hypothesized that increased reactive oxygen species (ROS) contributed to impaired renal autoregulatory capability in IR rats. Afferent arteriolar autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. IR was induced by 60 min of bilateral renal artery occlusion followed by 24 h of reperfusion. Afferent arterioles from sham rats exhibited normal autoregulatory behavior. Stepwise increases in perfusion pressure caused pressure-dependent vasoconstriction to 65 ± 3% of baseline diameter (13.2 ± 0.4 μm) at 170 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in IR rats. Baseline diameter averaged 11.7 ± 0.5 μm and remained between 90% and 101% of baseline over 65–170 mmHg, indicating impaired autoregulatory function. Acute antioxidant administration (tempol or apocynin) to IR kidneys for 20 min increased baseline diameter and improved autoregulatory capability, such that the pressure-diameter profiles were indistinguishable from those of sham kidneys. Furthermore, the addition of polyethylene glycol superoxide dismutase or polyethylene glycolcatalase to the perfusate blood also restored afferent arteriolar autoregulatory responsiveness in IR rats, indicating the involvement of superoxide and/or hydrogen peroxide. IR elevated mRNA expression of NADPH oxidase subunits and monocyte chemoattractant protein-1 in renal tissue homogenates, and this was prevented by tempol pretreatment. These results suggest that ROS accumulation, likely involving superoxide and/or hydrogen peroxide, impairs renal autoregulation in IR rats in a reversible fashion. NEW & NOTEWORTHY Renal ischemia-reperfusion (IR) leads to renal microvascular dysfunction manifested by impaired afferent arteriolar autoregulatory efficiency. Acute administration of scavengers of reactive oxygen species, polyethylene glycol-superoxide dismutase, or polyethylene glycol-catalase following renal IR restored afferent arteriolar autoregulatory capability in IR rats, indicating that renal IR led to reversible impairment of afferent arteriolar autoregulatory capability. Intervention with antioxidant treatment following IR may improve outcomes in patients by preserving renovascular autoregulatory function and potentially preventing the progression to chronic kidney disease after acute kidney injury. [ABSTRACT FROM AUTHOR]

Injured tubule epithelium stimulates a profibrotic milieu that accelerates loss of function in chronic kidney disease (CKD). This study tested the role of signal transducer and activator of transcription 1 (STAT1) in the progressive loss of kidney function in aristolochic acid (AA) nephropathy, a model of CKD. Mean serum creatinine concentration increased in wild-type (WT) littermates treated with AA, whereas Stat1-/- mice were protected. Focal increases in the apical expression of kidney injury molecule (KIM)- 1 were observed in the proximal tubules of WT mice with AA treatment but were absent in Stat1-/- mice in the treatment group as well as in both control groups. A composite injury score, an indicator of proximal tubule injury, was reduced in Stat1-/- mice treated with AA. Increased expression of integrin-b6 and phosphorylated Smad2/3 in proximal tubules as well as interstitial collagen and fibronectin were observed in WT mice following AA treatment but were all decreased in AA-treated Stat1-/- mice. The data indicated that STAT1 activation facilitated the development of progressive kidney injury and interstitial fibrosis in AA nephropathy. [ABSTRACT FROM AUTHOR]