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Jaimes EA, Zhou MS, Pearse DD, Puzis L, Raij L. Upregulation of cortical COX-2 in salt-sensitive hypertension: role of angiotensin II and reactive oxygen species. Am J Physiol Renal Physiol 294: F385-F392, 2008. First published December 19, 2007; doi: 10.1152/ajprenal.00302.2007.—Salt-sensitive (SS) hypertension is a vascular diathesis characterized by reduced cardiovascular and renal nitric oxide bioavailability and local upregulation of ANG II. We have demonstrated that rats infused with ANG II manifest increased cortical cyclooxygenase (COX)-2 expression and activity via NADPH oxidase-derived reactive oxygen species (ROS). In the present studies we used Dahl salt-sensitive (DS) rats to test the hypothesis that hypertensive SS rats have increased cortical COX-2 upregulation, which is mediated by ANG II and ROS. DS rats were placed on either a normal-salt diet (0.5% NaCl) or a high-salt diet (4% NaCI) for 6 wk and treated with either the ANG II type 1 (AT1) receptor blocker candesartan (Can, 10 mg·kg-1·day-1) or the SOD mimetic tempol (1 mmol/l). Hypertensive SS rats had a twofold increase in the cortical expression of COX-2 as assessed by Western blot. These changes in COX-2 expression were accompanied by a 10-fold increase in COX-2 mRNA expression and a 2-fold increase in the urinary excretion of PGE2. Treatment with either the AT1 receptor blocker Can or the SOD mimetic tempol did not reduce blood pressure but resulted in significant reductions in the cortical expression of COX-2 and the urinary excretion of PGE2. In conclusion, we have demonstrated that local activation of the renin-angiotensin system, via increased ROS generation, mediates COX-2 upregulation in hypertensive SS rats. These studies unveil novel mechanistic pathways that may play a role in the pathogenesis of hypertensive renal injury. [ABSTRACT FROM AUTHOR]

L-arginine is a semi essential amino acid and also a substrate for the synthesis of nitric oxide (NO), polyamines, and agmatine. These L-arginine metabolites may participate in the pathogenesis of renal disease and constitute the rationale for manipulating L-arginine metabolism as a strategy to ameliorate kidney disease. Modification of dietary L-arginine intake in experimental models of kidney diseases has been shown to have both beneficial as well as deleterious effects depending on the specific model studied. L-arginine supplementation in animal models of glomerulonephritis has been shown to be detrimental, probably by increasing the production of NO from increased local expression of inducible NO synthase (iNOS). L-arginine supplementation does not modify the course of renal disease in humans with chronic glomerular diseases. However, beneficial effects of L-arginine supplementation have been reported in several models of chronic kidney disease including renal ablation, ureteral obstruction, nephropathy secondary to diabetes, and salt-sensitive hypertension. L-arginine is reduced in pre- eclampsia and recent experimental studies indicate that L-arginine supplementation may be beneficial in attenu- ating the symptoms of preeclampsia. Administration of exogenous L-arginine has been shown to be protective in ischemic acute renal failure. In summary, the role of L-arginine in the pathogenesis and treatment of renal disease is not completely understood and remains to be established. [ABSTRACT FROM AUTHOR]

Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl salt-sensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaCl) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 ± 8 vs. 150 ± 2 mmHg in normal salt diet (0.5% NaCI), P < 0.05], glomerulosclerosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-F2α-isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-β (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (-44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg·kg-1·day-1) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-β1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 ± 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-β 1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system. [ABSTRACT FROM AUTHOR]