Zhao Chuanyan, Chen Zhuyun, Xu Xueqiang, An Xiaofei, Duan Suyan, Huang Zhimin, Zhang Chengning, Wu Lin, Zhang Bo, Zhang Aihua, Xing Changying, Yuan Yanggang
Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China.
Exp Cell Res. 2017 Jan 15;350(2):390-397. doi: 10.1016/j.yexcr.2016.12.015. Epub 2016 Dec 23.
Cisplatin often causes acute kidney injury (AKI) in the treatment of a wide variety of malignancies. Mitochondrial dysfunction is one of the main reasons for cisplatin nephrotoxicity. Previous study showed that Pink1 and Parkin play central roles in regulating the mitophagy, which is a key protective mechanism by specifically eliminating dysfunctional or damaged mitochondria. However, the mechanisms that modulate mitophagy in cisplatin induced nephrotoxicity remain to be elucidated. The purpose of this study was to investigate the effects of Pink1/Parkin pathway in mitophagy, mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. In cultured human renal proximal tubular cells, we found that knockdown of Pink1/Parkin induced the aggravation of mitochondrial function, leading to the increase of cell injury through inhibition of mitophagy. Additionally, the overexpression of Pink1/Parkin protected against cisplatin-induced mitochondrial dysfunction and cell injury by promoting mitophagy. Our results provide clear evidence that Pink1/Parkin-dependent mitophagy has identified potential targets for the treatment of cisplatin-induced AKI.
顺铂在多种恶性肿瘤的治疗中常导致急性肾损伤（AKI）。线粒体功能障碍是顺铂肾毒性的主要原因之一。先前的研究表明，Pink1和Parkin在调节线粒体自噬中起核心作用，线粒体自噬是一种通过特异性清除功能失调或受损线粒体的关键保护机制。然而，在顺铂诱导的肾毒性中调节线粒体自噬的机制仍有待阐明。本研究的目的是探讨Pink1/Parkin通路在顺铂治疗期间对线粒体自噬、线粒体功能障碍和肾近端小管细胞损伤的影响。在培养的人肾近端小管细胞中，我们发现敲低Pink1/Parkin会导致线粒体功能恶化，通过抑制线粒体自噬导致细胞损伤增加。此外，Pink1/Parkin的过表达通过促进线粒体自噬来保护细胞免受顺铂诱导的线粒体功能障碍和细胞损伤。我们的结果提供了明确的证据，即Pink1/Parkin依赖性线粒体自噬已成为治疗顺铂诱导的AKI的潜在靶点。
