Uncoupling protein 1 inhibits mitochondrial reactive oxygen species generation and alleviates acute kidney injury
Uncoupling protein 1 inhibits mitochondrial reactive oxygen species generation and alleviates acute kidney injury
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解偶联蛋白1抑制线粒体活性氧的产生并减轻急性肾损伤
DOI：
10.1016/j.ebiom.2019.10.023
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发表时间：
2019-11-01
期刊：
影响因子：
11.1
通讯作者：
Ding, Xiaoqiang
中科院分区：
文献类型：
--
作者：
Jia, Ping;Wu, Xiaoli;Ding, Xiaoqiang
背景：解偶联蛋白1 （Uncoupling protein 1, UCP1）主要存在于棕色脂肪组织线粒体中，通过线粒体功能性解偶联介导能量耗散产生热量，而不是ATP。然而，其在肾脏中的表达和功能尚不清楚。方法：对缺血再灌注（IR）损伤小鼠肾脏进行mRNA微阵列分析。发现了IR后下调幅度最大的基因UCP1，并在体外和体内评估了其在线粒体活性氧（ROS）产生和氧化应激损伤中的作用。我们利用UCP1基因缺失来研究UCP1对小鼠缺血或顺铂性急性肾损伤（AKI）的影响。结果：UCP1位于肾脏肾小管上皮细胞中，在肾脏IR期间呈时间依赖性下调。UCP1缺失增加肾脏氧化应激，加重小鼠缺血或顺铂诱导的AKI。基于病毒的UCP1过表达减少了缺氧处理的小管上皮细胞线粒体ROS的产生和凋亡。此外，在肾脏IR期间，UCP1的表达受到过氧化物酶体增殖激活物受体(PPAR) γ的调节。ppar - γ在体外的过表达与ucp1过表达表型相似。在UCP1（+/+）小鼠中，ppar - γ激动剂可诱导UCP1上调并对肾IR损伤提供保护作用，而在UCP1（-/-）小鼠中则无此作用。解释：UCP1可能通过抑制氧化应激来预防AKI，激活UCP1代表了AKI的潜在治疗策略。基金：国家自然科学基金资助，上海市科学技术委员会。(c) 2019年作者。Elsevier B.V.出版
Background: Uncoupling protein 1 (UCP1) is predominantly found in brown adipose tissue mitochondria, and mediates energy dissipation to generate heat rather than ATP via functional mitochondrial uncoupling. However, little is known about its expression and function in kidney.Methods: We carried out a mRNA microarray analysis in mice kidneys with ischemia reperfusion (IR) injury. The most dramatically downregulated gene UCP1 after IR was identified, and its role in generation of mitochondrial reactive oxygen species (ROS) and oxidative stress injury was assessed both in vitro and in vivo. Genetic deletion of UCP1 was used to investigate the effects of UCP1 on ischemia or cisplatin-indued acute kidney injury (AKI) in mice.Findings: UCP1 was located in renal tubular epithelial cells in kidney and downregulated in a time-dependent manner during renal IR. Deletion of UCP1 increased oxidative stress in kidneys and aggravated ischemia or cisplatin induced AKI in mice.Viral-based overexpression of UCP1 reduced mitochondrial ROS generation and apoptosis in hypoxia-treated tubular epithelial cells. Furthermore, UCP1 expression was regulated by peroxisome proliferator-activator receptor (PPAR) gamma in kidneys during renal IR. Overexpression of PPAR-gamma resembled UCP1-overexpression phenotype in vitro. Treatment with PPAR-gamma agonist could induce UCP1 upregulation and provide protective effect against renal IR injury in UCP1(+/+) mice, but not in UCP1(-/-) mice.Interpretation: UCP1 protects against AKI likely by suppressing oxidative stress, and activation of UCP1 represents a potential therapeutic strategy for AKI. Fund: National Natural Science Foundation of China grants, Science and Technology Commission of Shanghai. (c) 2019 The Authors. Published by Elsevier B.V.