Renal Effects of HMG-CoA Reductase Inhibition in a Rat Model of Chronic Inhibition of Nitric Oxide Synthesis

Abstract

Background/Aims: In addition to their lipid-lowering effects, HMG-CoA reductase inhibitors (statins) induce a variety of pleiotropic actions that have been recently studied in the area of cardiovascular and renal protection. In the present studies we sought to determine whether statins retain beneficial effects in the experimental model of NO deficiency achieved by chronic administration of a pressor dose of L-arginine analogue N-nitro-L-arginine-methyl ester (L-NAME). Methods: To address this issue, blood pressure (BP), renal function (GFR), and albuminuria were determined in rats treated for 4 weeks with L-NAME, L-NAME + atorvastatin (ATO), and in untreated controls. In addition, renal cortical protein expression of caveolin 1 (CAV1), vascular endothelial growth factor (VEGF), and activity of RhoA were also determined. Results:L-NAME administration resulted in sustained elevation of BP, decreased GFR, and in higher albuminuria as compared to control animals. Co-administration of ATO with L-NAME normalized albuminuria and prevented decreases in GFR in L-NAME rats without having an impact on pressor effects of L-NAME. CAV1 protein expression was similar in all groups of rats. In contrast, VEGF expression and RhoA activity was increased in L-NAME-treated animals, and normalized with co-administration of ATO. Conclusion: Treatment with ATO exerts early nephroprotective effects in the NO-deficient model of hypertension. These effects could be mediated by amelioration of VEGF expression and reduction of RhoA activity.

Pitavastatin Exhibits Protective Effects on Podocytes Accompanied by BMP-7 Up-Regulation and Rho Suppression

“…Recent experimental and clinical studies demonstrated that these effects of statins, called pleiotropic effects, contribute to renal protection [11,25,26,33] . In this study, pitavastatin significantly improved indices of diabetic nephropathy, such as urinary protein excretion, plasma creatinine, and CCr.…”

Effect of statin therapy on contrast-induced nephropathy after coronary angiography: A meta-analysis

“…nitric oxide bioavailability, attenuating production of reactive oxygen species, and protecting against complement-mediated injury [31]. In addition, experimental data have shown that statins exert renoprotective effects in a rat model of long-term inhibition of nitric oxide synthesis by amelioration of vascular endothelial growth factor expression and decrease of RhoA activity [32].…”

Atorvastatin upregulates nitric oxide synthases with Rho-kinase inhibition and Akt activation in the kidney of spontaneously hypertensive rats

“…Therefore, it is possible that the statin-upregulated nitric oxide system in the kidney, especially in the renal medulla, may contribute to the antihypertensive effect of statins through increased medullary blood flow and inhibited Na reabsorption in the medullary TAL and collecting duct of SHRs. Indeed, several studies reported that statins did not reduce the blood pressure in L-NAME-induced hypertensive rats [40,41] or angiotensin II-treated eNOS knockout mice [42]. Nitric oxide-dependent mechanisms have important roles not only in the antihypertensive effect of statins but also in the renoprotective effect of statins.…”

“…rats [40,41] and angiotensin II-treated eNOS knockout mice [42]. Inhibition of Rho/Rho-kinase pathway by statins may contribute not only to the upregulation of eNOS expression and activity but also to benefits in cardiovascular disease [44].…”