MO079: Treatment with Nebivolol Ameliorates Renovascular Alterations and Oxidative Stress in Tenofovir-Induced Nephrotoxicity in Rats

Abstract

Abstract BACKGROUND AND AIMS Human immunodeficiency virus (HIV) continues to be a major global public health issue, having claimed millions of lives so far. Tenofovir disoproxil fumarate (TDF), a widely prescribed component in antiretroviral regimens for HIV treatment, has been associated with nephrotoxicity. Nebivolol (NBV) is a third generation selective β-1 adrenergic receptor blocker currently used in the treatment of hypertension and cardiovascular diseases. The potential mechanisms by which NBV may protect renal structure and function include suppression of oxidative stress and enhancement of nitric oxide synthesis. The aim of this study was to investigate whether NBV could be an effective therapeutic option to mitigate TDF-induced nephrotoxicity. METHOD We divided Wistar rats into four groups: control (C, n = 8), received a standard diet for 30 days; TDF (n = 9), received a standard diet with the addition of TDF (300 mg/kg food) for 30 days; NBV (n = 8), received a standard diet for 30 days with the addition of NBV (100 mg/kg food) in the last 15 days; and TDF + NBV (n = 9), received a standard diet with the addition of TDF for 30 days and NBV in the last 15 days. We evaluated inulin clearance (GFR); tubular injury; mean arterial pressure (MAP); renal blood flow (RBF) and calculated renal vascular resistance (RVR); plasma and tissue angiotensin II (AIIp and AIIt, respectively); plasma aldosterone; plasma asymmetric dimethylarginine (ADMA); plasma and urinary thiobarbituric acid reactive substances (TBARSp and TBARSu, respectively); and whole blood glutathione (GSH). In renal tissue, we immunoblotted for endothelial nitric oxide synthase (eNOS), p47phox and p67phox. Data are expressed as mean ± SEM. RESULTS TDF + NBV rats showed an improvement in renal function, a normalization of MAP and attenuation in renal vasoconstriction, evidenced by increased RBF and diminished RVR. Administration of NBV also reduced AII and aldosterone levels in TDF-treated animals. Furthermore, the TDF + NBV group showed a lower plasma ADMA concentration and a higher protein expression of eNOS. Treatment with NBV was responsible for the maintenance of an adequate balance of TBARS and GSH levels, and it was associated with reductions in renal p47phox and p67phox. All results are described in Table 1. CONCLUSION Our data demonstrated the protective role of NBV in TDF-induced nephrotoxicity. The beneficial effects of NBV include a reduction in oxidative stress and RAAS activation, as well as a decrease in endothelial dysfunction, observed by an upregulation on the NO cascade. Therefore, NBV may be an effective therapeutic strategy in the treatment of patients with TDF-induced nephrotoxicity. Financial support: CAPES and FAPESP (2019/20840–0, 2018/12297–1, 2018/04930–6).