Interferon-γ is protective in cisplatin-induced renal injury by enhancing autophagic flux

The chemotherapeutic agent cisplatin often causes severe renal dysfunction; however, the molecular mechanism causing renal injury remains unclear. In wild-type mice, intrarenal interferon (IFN)-gamma gene expression was found to be enhanced while CD3(+) T cells and Ly-6G neutrophils were the main cellular source of IFN-gamma following cisplatin injection. Compared to wild-type mice, cisplatin-treated IFN-gamma-deficient (IFN-gamma(-/-)) mice exhibited exaggerated histopathological changes with higher blood urea nitrogen and creatinine levels. Cisplatin-induced apoptosis was associated with enhanced caspase-3 activation in renal proximal tubular epithelial cells, with effects suppressed by IFN-gamma resulting in increased cell viability. IFN-gamma significantly reduced the levels of the autophagic markers LC3-II and p62, and enhanced cathepsin D expression in cisplatin-treated renal proximal tubule epithelial cells, implying that IFN-gamma can accelerate autophagic flux. Tubular cell apoptosis was more evident with enhanced caspase-3 activation in IFN-gamma-deficient compared to wild-type mice. Elevated intrarenal LC3-II and increased p62 accumulation were associated with reduced cathepsin D activation in IFN-gamma-deficient mice, implying that the absence of IFN-gamma suppressed autophagic flux. Thus, IFN-gamma can accelerate autophagic flux by augmenting cathepsin D levels and reciprocally increasing the viability of renal tubular cells, thereby attenuating cisplatin-induced acute renal injury. Kidney International (2012) 82, 1093-1104; doi:10.1038/ki.2012.240; published online 11 July 2012