Nitrate attenuates cisplatin-induced acute kidney injury by promotion of mitophagy and reduction of oxidative stress
Haibo Wang, Chunyan Song, Feng Chen, Xiu Liu, Liang Hu, Chunmei Zhang, Songlin Wang, Wenbin Li
Current Medicine ›› 2023, Vol. 2 ›› Issue (1) : 8.
Nitrate attenuates cisplatin-induced acute kidney injury by promotion of mitophagy and reduction of oxidative stress
Cisplatin, an anticancer drug, has limited its clinical application due to its severe nephrotoxicity, such as acute kidney injury (AKI). Damaged or dysfunctional mitochondria caused by cisplatin are toxic to the cell by producing reactive oxygen species and releasing cell death factors. Mitophagy is the mechanism of selective degradation of these damaged mitochondria via autophagy, that is critical to cellular homeostasis and viability. In this study, the protective functions of inorganic nitrate against cisplatin-induced nephrotoxicity are assessed. Our results in vitro show that nitrate significantly reduced the apoptosis of HK2 or NRK52E cells induced by cisplatin treatment. Furthermore, dietary nitrate notably alleviates the tubular and glomerular damages as well as the loss of renal function in cisplatin-induced AKI mice models. These protective effects are closely related to downregulation of cell apoptosis and reduction of reactive oxygen species (ROS) generation. Mechanistically, inorganic nitrate treatment promotes the activation of mitophagy mediated by the PINK1-PRKN/PARK2 pathway, which plays an important role in the maintenance of mitochondrial quality, helping renal tubular cells to survive and recover from cisplatin stress. These novel findings suggest that inorganic nitrate supplementation deserve further exploration as a potential treatment in patients with cisplatin-induced renal injury.
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