Effects of Losartan, Tempol, and Their Combination On Renal Nitric Oxide Synthases in the Animal Model of Chronic Kidney Disease

Abstract

Down-regulation of nitric oxide synthase (NOS) and NO deficiency in the kidneys have been implicated in the pathogenesis of chronic kidney disease (CKD). In this study we examined the effects of losartan, tempol, and combined treatment on three NOS isoforms expressions, kidney NO content and NOS correlation with renal function and structure in the early stage of adriamycin (ADR)-induced CKD in spontaneously hypertensive rats (SHR). Rats were divided into control group, and four other groups which were treated with ADR and received vehicle, losartan (L, angiotensin II type 1 receptor blocker), tempol (T, redox-cycling nitroxide) or T+L treatment (by gavage) in a six-week study. Reduction of all NOS isoforms expressions were significantly improved by losartan or tempol, and correlated with proteinuria amelioration. Combined treatment induced down-regulation of constitutive NOS isoforms, whilst inducible NOS was up-regulated and followed by increased nitrite content and a significant decline in the glomerular filtration rate. Losartan or tempol prevented ADR-induced neoexpression of vimentin in the glomeruli and tubulointerstital areas, whereas de novo vimentin expression was still observed in the atrophic tubules and in the interstitial fibroblasts and myofibroblasts in combined treatment. It can be concluded that single treatments, contrary to combined, were effective in improving NO bioavailability and slowing down the progression of CKD.

Keywords

• adriamycin nephropathy
• hypertension
• nitric oxide synthase
• losartan
• tempol