No abstract

Cisplatin chemotherapy often causes acute kidney injury (AKI) in cancer patients. There is increasing evidence that mitochondrial dysfunction plays an important role in cisplatin-induced nephrotoxicity. Degradation of damaged mitochondria is carried out by mitophagy. Although mitophagy is considered of particular importance in protecting against AKI, little is known of the precise role of mitophagy and its molecular mechanisms during cisplatin-induced nephrotoxicity. Also, evidence that activation of mitophagy improved mitochondrial function is lacking. Furthermore, several evidences have shown that mitochondrial fission coordinates with mitophagy. The aim of this study was to investigate whether activation of mitophagy protects against mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. The effect of mitochondrial fission on mitophagy was also investigated. In cultured human renal proximal tubular cells, we observed that 3-methyladenine, a pharmacological inhibitor of autophagy, blocked mitophagy and exacerbated cisplatin-induced mitochondrial dysfunction and cells injury. In contrast, autophagy activator rapamycin enhanced mitophagy and protected against the harmful effects of cisplatin on mitochondrial function and cells viability. Suppression of mitochondrial fission by knockdown of its main regulator dynamin-related protein-1 (Drp1) decreased cisplatin-induced mitophagy. Meanwhile, Drp1 suppression protected against cisplatin-induced cells injury by inhibiting mitochondrial dysfunction. Our results provide evidence that Drp1-depedent mitophagy has potential as renoprotective targets for the treatment of cisplatin-induced AKI.

Podocytes play an important role in the pathogenesis and progression of glomerulosclerosis. Recent studies indicate that aldosterone/mineralocorticoid receptor (MR) is a major contributor of chronic kidney disease (CKD) progression. Aldosterone/MR induces glomerular podocyte injury, causing the disruption of the glomerular filtration barrier and proteinuria. The present study investigated the mechanisms by which aldosterone/MR mediated podocyte injury, focusing on the involvement of oxidative stress, endoplasmic reticulum (ER) stress, and autophagy. We observed that aldosterone/ MR induced ER stress and podocyte injury both in vivo and in vitro. Blockade of ER stress significantly reduced aldosterone/ MR-induced podocyte injury. In addition, we found that ER stress-induced podocyte injury was mediated by CCAAT/ enhancer-binding protein (C/EBP) homologous protein (Chop). Interestingly, autophagy was also enhanced by aldosterone/MR. Pharmacological inhibition of autophagy resulted in increased apoptosis. Inhibition of ER stress significantly reduced aldosterone/MR-induced autophagy. In addition, the activation of ER stress increased the formation of autophagy, which protected podocytes from apoptosis. Moreover, we observed that the addition of ROS scavenger, N-acetyl cystein (NAC), blocked both ER stress and autophagy by aldosterone/MR. Collectively, these results suggest that oxidant stress-mediated aldosterone/MR-induced podocyte injury via activating ER stress, which then triggers both Chop-dependent apoptosis and autophagy to cope with the injury. These findings may guide us to therapeutic strategies for glomerular diseases.