Abstract
Cisplatin is a widely used chemotherapeutic drug with notorious toxicity in the kidneys, which involves mitochondrial dysfunction and damage in renal tubular cells. Mitophagy is a form of selective autophagy that removes damaged or dysfunctional mitochondria to maintain cellular homeostasis. In this study, we have used mouse and cell models to examine the role and regulation of mitophagy in cisplatin nephrotoxicity. Cisplatin treatment was associated with the activation of autophagy and mitophagy. Rapamycin, a pharmacological inhibitor of mTOR, stimulated autophagy and mitophagy, and alleviated the development of cisplatin nephrotoxicity. PINK1 and Parkin were increased in kidney tissues during cisplatin treatment of mice. In PINK1 or Parkin gene knockout mouse models, both basal and cisplatin-induced mitophagy in kidneys were defective. Compared with wild-type littermates, PINK1 and Parkin knockout mice showed more severe renal functional loss, tissue damage, and apoptosis during cisplatin treatment. The results suggest that PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity and has a protective role against kidney injury.
Highlights
Cisplatin is a widely used chemotherapy drug for the treatment of cancers of the testis, ovary, breast, lung, and other origins[1,2]
PINK1/Parkin-dependent mitophagy is induced during cisplatin treatment in Boston University mouse proximal tubular (BUMPT) cells We initially examined the PINK1/Parkin-mediated pathway of mitophagy during cisplatin treatment of BUMPT cells
In cisplatintreated cells, some LC3-GFP-labeled puncta/autophagosomes co-localized with Mito-Tracker-labeled mitochondria (Fig. 1e), indicating mitophagy. These results provided the evidence of the activation of autophagy and mitophagy during cisplatin treatment of BUMPT cells, which was accompanied by the development of apoptosis
Summary
Cisplatin is a widely used chemotherapy drug for the treatment of cancers of the testis, ovary, breast, lung, and other origins[1,2]. Damage and dysfunction of mitochondria have an important role in the pathogenesis of renal diseases, including acute kidney injury (AKI) induced by renal ischemia–reperfusion, sepsis, and nephrotoxins[10,11,12,13,14]. These conditions are associated with the pathological changes of mitochondrial structure and function in kidney tissues, especially in renal tubules. Mitochondrial dysfunction would result in oxidative stress, inflammation, and cell death, inducing a rapid deterioration in renal function This seems particular true for cisplatin-induced AKI or nephrotoxicity[3,4,5,6]
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