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)-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.
Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
Akihiko
A
Kimura
Yuko
Y
Ishida
Michiya
M
Inagaki
Yasushi
Y
Nakamura
Tokio
T
Sanke
Naofumi
N
Mukaida
Toshikazu
T
Kondo
D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001343:Autophagy; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D017252:CD3 Complex / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002945:Cisplatin; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007684:Kidney Tubules / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
D000950:Antigens, Ly; D015415:Biomarkers; D017252:CD3 Complex; C480309:Ly6G antigen, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D007371:Interferon-gamma; D003404:Creatinine; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002402:Cathepsin D; C533923:Ctsd protein, mouse; D002945:Cisplatin