PROTECTIVE EFFECT OF N-ACETYLCYSTEINE ON CHRONIC TENOFOVIR NEPHROTOXICITY IN RATS

Abstract

Introduction and Aims:Tenofovir is an effective drug for HIV infection and chronic hepatitis B. This antiretroviral drug is associated to chronic kidney disease and increased oxidative stress. N-acetylcysteine (NAC) has been shown to be a potent antioxidant by increasing gluthatione levels. Previous study from our Laboratory demonstrated that NAC attenuates the progression of chronic renal failure in rats submitted to 5/6 nephrectomy (Kidney Int 2005;68:2208-17). The aim of this study was to evaluate the effect of chronic use of tenofovir on renal function and oxidative stress in rats, and a possible protector effect of the association of N-acetylcysteine (NAC) against Tenofovir nephrotoxicity. Methods:Three groups of 2-mo-old male Wistar rats were studied: 1- control (n=7); 2- Tenofovir ( 50mg/kg diet, n=10) 3- Tenofovir (50 mg/Kg diet) + NAC (600 mg/L drinking water, n=10). The rats were monitored during 4 months, after which clearance studies were performed. Twenty four hours prior to clearance studies, the animals were housed in metabolic cages to collect 24h urine volume. The rats were anesthetized to measured inulin clearance (GFR, ml/min/100 gBW), blood pressure (BP, mmHg), renal blood flow (RBF, ml/min flowmeter) and calculated renal vascular resistance (RVR, mmHg/ml/min). Oxidative stress was evaluated by serum thiobarbituric acid reactive substances, a marker of lipid peroxidation (TBARS, nM/mL), urinary TBARS excretion (nM/24h) and by the endogenous antioxidant, serum gluthatione (μM/mL). Renal tissue was immunoblotted for angiotensin II. Results:Body weight, water and food ingestion were not different among the 3 groups. The mean daily Tenofovir ingestion was 1.30±0.12 mg in Tenofovir group and 1.32±0.08mg in Tenofovir+NAC (not significant). The mean daily NAC dose was 28.8±3.0 mg. Chronic Tenofovir administration decreased GFR, increased mean arterial pressure and renal vascular resistance. All these effects were associated with increased oxidative stress and were reversed in the Tenofovir + NAC group. Conclusions:Chronic administration of Tenofovir leads to a decrease in glomerular filtration rate, increase in blood pressure, renal tissue angiotensin II and oxidative stress. NAC association has a protective effect attributable to lower levels of lipid peroxidation and higher levels of gluthatione. These findings have significant clinical implications for renal protection against Tenofovir nephrotoxicity.