Short-term control of diet affects cisplatin-induced acute kidney injury through modulation of mitochondrial dynamics and mitochondrial GSH

Abstract

Obesity affects acute kidney injury (AKI) induced by various clinical settings, including transplantation and cisplatin-cancer therapy. However, the effect of short-term food intake change remains to be defined. Here, we investigated the effects of short-term high-fat diet intake and food restriction on cisplatin-induced AKI. Mice were fed either a high-fat diet (HFD) or a low-fat diet (LFD) for 11 days or were not fed for 40 hh (fasting), before cisplatin administration. Cisplatin-induced functional and structural damages to kidneys in both HFD- and LFD-fed mice, with greater damages in HFD-fed mice than LFD-fed mice. HFD decreased mitochondrial total glutathione (tGSH) level, along with increases in the plasma and kidney cholesterol levels. Cisplatin caused the increase of kidney cholesterol levels and oxidative stress, along with the decrease of mitochondrial tGSH levels. In addition, cisplatin-induced mitochondrial damage and apoptosis of tubular cells in both HFD- and LFD-fed mice. An increase of Fis1 (mitochondria fission 1 protein), whereas a decrease of Opa1 (mitochondria fusion 1 protein) occurred by cisplatin. These cisplatin effects were greater in HFD-fed mice than in LFD-fed mice. Administration of mitochondria-specific antioxidant treatment during HFD feeding inhibited these cisplatin-induced changes. Fasting for 40 h also significantly reduced the cisplatin-induced changes mentioned above. These data demonstrate that short-term HFD intake worsens cisplatin-induced oxidative stress by the reduction of mitochondrial tGSH, resulting in increased cisplatin-induced nephrotoxicity. These data newly indicate that the control of calorie intake, even for a short period, affects kidney susceptibility to injury. Although most studies described the effects of a long-term high-fat diet on the kidneys, in this study, we found that even if a high-fat diet was consumed for a short-term, physiological changes and mitochondria tGSH decrease in the kidneys, and consequently increased cisplatin-nephrotoxic susceptibility. These data suggest the association of calorie intake with kidney susceptibility to cisplatin.