PINK1 Deficiency Ameliorates Cisplatin-Induced Acute Kidney Injury in Rats
PINK1 Deficiency Ameliorates Cisplatin-Induced Acute Kidney Injury in Rats
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PINK1 缺陷可改善顺铂引起的大鼠急性肾损伤
DOI：
10.3389/fphys.2019.01225
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发表时间：
2019-09
影响因子：
4
通讯作者：
Chuan Qin
中科院分区：
文献类型：
--
作者：
Li Zhou;Ling Zhang;Yu Zhang;Xuan Yu;Xiuping Sun;Tao Zhu;Xianglei Li;Wei Liang;Yunlin Han;Chuan Qin
线粒体自噬在清除受损和去极化的线粒体以维持细胞内稳态和活力中起关键作用。虽然最初发现于神经退行性疾病，但据报道线粒体自噬在急性肾损伤中起重要作用。PINK 1和Parkin是线粒体自噬途径中的关键分子。在这里，我们使用PINK 1基因敲除大鼠来研究PINK 1/Parkin介导的线粒体自噬在顺铂肾毒性中的作用。顺铂治疗后，与野生型大鼠相比，PINK 1基因敲除大鼠显示出较低的血浆肌酐和较少的肾小管损伤。同时，在PINK 1敲除大鼠中，自噬体形成和LC 3B-II积累所指示的线粒体自噬也减弱。顺铂处理后肾脏PINK 1和Parkin表达下调，而BNIP 3L表达上调，提示BNIP 3/BNIP 3L通路在顺铂诱导的线粒体自噬中起重要作用。透射电子显微镜显示，PINK 1缺陷抑制顺铂诱导的线粒体片段化，表明线粒体融合和分裂的参与。采用实时荧光定量PCR和蛋白质印迹法检测肾脏线粒体动力学相关蛋白Fis 1、Drp 1、Mfn 1、Mfn 2和Opa 1的表达。结果表明，PINK 1缺陷明显阻止顺铂诱导的DRP 1上调。最后，PINK 1缺陷减轻顺铂诱导的肾小管凋亡通过TUNEL检测以及caspase 3和切割caspase 3的表达。总之，这些结果表明，PINK 1缺乏改善了顺铂诱导的大鼠急性肾损伤，可能是通过抑制DRP 1介导的线粒体分裂和过度的线粒体自噬。
Mitophagy plays a key role in cleaning damaged and depolarized mitochondria to maintain cellular homeostasis and viability. Although it was originally found in neurodegenerative diseases, mitophagy is reported to play an important role in acute kidney injury. PINK1 and Parkin are key molecules in mitophagy pathway. Here, we used PINK1 knockout rats to examine the role of PINK1/Parkin-mediated mitophagy in cisplatin nephrotoxicity. After cisplatin treatment, PINK1 knockout rats showed lower plasma creatinine and less tubular damage when compared with wild-type rats. Meanwhile, mitophagy indicated by autophagosome formation and LC3B-II accumulation was also attenuated in PINK1 knockout rats. Renal expression of PINK1 and Parkin were down-regulated while BNIP3L was up-regulated by cisplatin treatment, indicating a major role of BNIP3/BNIP3L pathway in cisplatin-induced mitophagy. Transmission electron microscopy showed that PINK1 deficiency inhibited cisplatin-induced mitochondrial fragmentation indicating an involvement of mitochondrial fusion and fission. Renal expression of mitochondrial dynamics related proteins including Fis1, Drp1, Mfn1, Mfn2, and Opa1 were checked by real-time PCR and western blots. The results showed PINK1 deficiency distinctly prevented cisplatin-induced up-regulation of DRP1. Finally, PINK1 deficiency alleviated cisplatin-induced tubular apoptosis indicated by TUNEL assay as well as the expression of caspase3 and cleaved caspase3. Together, these results suggested PINK1 deficiency ameliorated cisplatin-induced acute kidney injury in rats, possibly via inhibiting DRP1-mediated mitochondrial fission and excessive mitophagy.
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影响因子：
19.6
作者：
Kaushal GP;Shah SV
通讯作者：
Shah SV
影响因子：
4.5
作者：
Meyer JN;Leuthner TC;Luz AL
通讯作者：
Luz AL
影响因子：
19.6
作者：
通讯作者：
--
影响因子：
6.1
作者：
Yeh, Chung-Hsin;Hsu, Shih-Ping;Wang, Nai-Phog
通讯作者：
Wang, Nai-Phog
影响因子：
56.9
作者：
R. Gottlieb
通讯作者：
R. Gottlieb