Nephroprotective effects of nebivolol in 2K1C rats through regulation of the kidney ROS-ADMA-NO pathway

Background: To evaluate the protective effect of nebivolol against kidney damage and elucidate the underlying mechanism in a two-kidney, one-clip (2K1C) rat model. Methods: 2K1C rats were obtained by clipping left renal artery of male Wistar rats and were considered hypertensive when systolic blood pressure (SBP) was >= 160 mmHg 4 weeks after surgery. The 2K1C hypertensive rats were divided into untreated, nebivolol (10 mg/kg, ig), and atenolol (80 mg/kg, ig) treatment groups. The treatments lasted for 8 weeks. SBP, kidney structure and function, plasma and kidney angiotensin (Ang) II, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and the oxidant status were examined. Kidney protein expression of NADPH oxidase (Nox) isoforms and its subunit p22phox, nitric oxide synthase (NOS) isoforms, protein arginine N-methyltransferase (PRMT) 1, and dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 was tested by western blotting. Results: Nebivolol and atenolol exerted similar hypotensive effects. However, atenolol had little effect while nebivolol significantly ameliorated the functional decline and structural damage in the kidney, especially in non-clipped kidney (NCK), which was associated with the reduction of Ang II in NCK. Moreover, nebivolol inhibited the NCK production of reactive oxygen species (ROS) by decreasing Nox2, Nox4, and p22phox expression. Further, nebivolol reduced the plasma and kidney ADMA levels by increasing DDAH2 expression and decreasing PRMT1 expression. Nebivolol also increased the NCK NO level by ameliorating the expression of kidney NOS isoforms. Conclusions: Our results demonstrated that long-term treatment with nebivolol had renoprotective effect in 2K1C rats partly via regulation of kidney ROS-ADMA-NO pathway. (c) 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.