Mitochondrial pathway of apoptosis and necrosis contribute to tenofovir disoproxil fumarate-induced renal damage in rats.

ABSTRACT

Tenofovir disoproxil fumarate (TDF) is currently the only nucleotide analogue reverse-transcriptase inhibitor that is approved by the Food and Drug administration (FDA), USA, for the treatment of human immunodeficiency virus (HIV) infection. In recent days, renal toxicity is becoming common i HIV patients treated with TDF. However, the mechanism of tenofovir nephrotoxicity is not clear. We hypothesized that mitochondrial pathway of apoptosis, poly [ADP-ribose] polymerase (PARP) overactivation and neutrophil infiltration may contribute to tenofovir-induced renal damage. Renal damage was induced in adult male Wistar rats by the oral administration of 600 mg/kg body weight daily for five consecutive weeks. Kidneys were removed and used for histological and biochemical analyses. Apoptosis was detected by terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate nick end-labelling (TUNEL) assay and caspase 3 activity and protein expression; mitochondrial pathway of apoptosis by cyt c release; and PARP activation by immunofluorescence, immunohistochemistry and Western blot techniques. Myeloperoxidase (MPO) activity was measured as a marker of neutrophil infiltration. TDF administration resulted in increased number of TUNEL-positive cells, activation of caspase 3 and release of cyt c from mitochondria into the cytosol in the kidneys. There was increased nuclear localization of PARP as well as increase in its protein level in the TDF-treated rat kidneys. In addition, renal MPO activity was increased ninefold as compared to controls. The results of the present study show that mitochondrial apoptotic pathway, PARP overactivation and neutrophil infiltration contribute to tenofovir-induced renal damage in rats.