Cell stress, hypoxic response and apoptosis in murine adriamycin-induced nephropathy

Abstract

Adriamycin (ADR)-induced nephropathy in rodents is an experimental model commonly used for studies of chronic human renal diseases. The molecular associations involved in renal apoptosis linked to hypoxia and cell stress response in this model are not completely known. The aim of this study was to determine the associations among the expression patterns of the Inducible Nitric Oxide Synthase (iNOS), the heat shock protein 60 (Hsp60) and the Hypoxia Inducible Factor-1 Alpha (HIF-1α) linked to apoptosis in renal cortex in the nephrotic syndrome progression induced by ADR administration. Male BALB/c mice were treated with a single dose of ADR (11 mg kg-1; i.v.). Tubulointerstitial nephrosis was monitored by histopathological assessment and by biochemical determinations on 7, 15 and 30 days following drug exposure. These results were evaluated in conjunction with renal expression of iNOS, Hsp60 and HIF-1α. Cortical apoptosis was examined by TUNEL assay. The increment of renal apoptotic cells in tubulointerstitial areas was accompanied by the decrease in Bcl-xL/Bax ratio and the enhancement of the active caspase-3 and Hsp60 expressions from day 7 onwards. iNOS and HIF-1α increased concomitant with the renal apoptosis and the tubule interstitial injury. Taking the previous information into account, data indicate that the over expression of renal HIF-1α, iNOS and Hsp60 are concurrent with the apoptotic events triggered by ADR. These results contribute to additional knowledge of the molecular complex events involved in the context of ADR-induced nephropathy progression.