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- Title
Interferon-γ is protective in cisplatin-induced renal injury by enhancing autophagic flux.
- Authors
Kimura A; Ishida Y; Inagaki M; Nakamura Y; Sanke T; Mukaida N; Kondo T; Kimura, Akihiko; Ishida, Yuko; Inagaki, Michiya; Nakamura, Yasushi; Sanke, Tokio; Mukaida, Naofumi; Kondo, Toshikazu
- Abstract
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)-γ gene expression was found to be enhanced while CD3(+) T cells and Ly-6G neutrophils were the main cellular source of IFN-γ following cisplatin injection. Compared to wild-type mice, cisplatin-treated IFN-γ-deficient (IFN-γ(-/-)) 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-γ resulting in increased cell viability. IFN-γ 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-γ can accelerate autophagic flux. Tubular cell apoptosis was more evident with enhanced caspase-3 activation in IFN-γ-deficient compared to wild-type mice. Elevated intrarenal LC3-II and increased p62 accumulation were associated with reduced cathepsin D activation in IFN-γ-deficient mice, implying that the absence of IFN-γ suppressed autophagic flux. Thus, IFN-γ 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.
- Publication
Kidney International, 2012, Vol 82, Issue 10, p1093
- ISSN
0085-2538
- Publication type
journal article
- DOI
10.1038/ki.2012.240