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Nebivolol ameliorated kidney damage in Zucker diabetic fatty rats by regulation of oxidative stress/NO pathway: Comparison with captopril

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Clinical and Experimental Pharmacology and Physiology

Published online on


--- - |2 Summary The aim was to evaluate the effects and mechanisms of nebivolol on renal damage in Zucker diabetic fatty (ZDF) rats, in comparison with those of atenolol and captopril. Animals were divided into: control lean Zucker rats, ZDF rats, ZDF rats orally treated with nebivolol (10 mg/kg), atenolol (100 mg/kg) or captopril (40 mg/kg) for 6 months. Systolic blood pressure (SBP), blood glucose, kidney structure and function, plasma and kidney levels of nitric oxide (NO) and asymmetric dimethylarginine (ADMA), and oxidant status were evaluated. Kidney expressions of adenosine monophosphate‐activated protein kinase (AMPK), NADPH oxidase (NOX) isoforms 2 and 4 and subunit p22phox, nitric oxide synthase (NOS) isoforms, endothelial NOS (eNOS) uncoupling, protein arginine N‐methyltransferase (PRMT) 1, and dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 were tested. All drugs induced a similar control of SBP. Nebivolol did not affect the increased plasma glucose. Unlike atenolol, nebivolol prevented the decrease in plasma insulin, and, like captopril, it reduced plasma lipid contents. Nebivolol ameliorated, to a greater extent than captopril, damages to renal structure and function, which were associated with an improvement in interlobular artery dysfunction. Nebivolol elevated kidney phosphorylation of AMPK, attenuated NOX4 and p22phox expression and oxidative stress marker levels. Nebivolol increased plasma and renal NO, enhanced expressions of eNOS, p‐eNOS and neuronal NOS, and suppressed eNOS uncoupling and inducible NOS expression. High ADMA in plasma and kidney were decreased by nebivolol through increasing DDAH2 and decreasing protein arginine N‐methyltransferase 1. Long‐term treatment of nebivolol ameliorated diabetic nephropathy, at least in part, via regulation of renal oxidative stress/NO pathway. - Clinical and Experimental Pharmacology and Physiology, EarlyView.