Estrogen-related receptor-alpha mediates puromycin aminonucleoside-induced mesangial cell apoptosis and inflammatory injury
Estrogen-related receptor-alpha mediates puromycin aminonucleoside-induced mesangial cell apoptosis and inflammatory injury
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雌激素相关受体 α 介导嘌呤霉素氨基核苷诱导的系膜细胞凋亡和炎症损伤。
DOI：
10.1152/ajprenal.00507.2018
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Huang Songming
中科院分区：
文献类型：
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作者：
Gong Wei;Song Jiayu;Chen Xi;Li Shuzhen;Yu Jing;Xia Weiwei;Ding Guixia;Zhang Yue;Jia Zhanjun;Zhang Aihua;Huang Songming
肾小球疾病是慢性肾脏疾病的主要病因，系膜细胞（MC）已被证明参与其发病机制。嘌呤霉素氨基糖苷（PAN）是一种肾毒性药物，其引起肾小球损伤的机制尚不清楚。本研究旨在探讨PAN在MC凋亡中的作用及其机制。我们发现PAN可诱导MC凋亡，并伴有细胞活力下降和炎症反应增强。凋亡调节因子BAX（BAX）和caspase-3表达的增加进一步证明了细胞凋亡。与PAN处理后MC中的凋亡反应一致，我们还发现在mRNA和蛋白水平上显着诱导雌激素相关受体α（ERRα），一种孤儿核受体。有趣的是，通过siRNA方法沉默ERRα导致PAN引起的细胞凋亡和炎症反应减弱。更重要的是，MC中ERRα的过表达显著地触发MC凋亡，与BAX和caspase-3表达的增加一致。在PAN处理的MC中，ERRα过表达进一步加重了PAN诱导的细胞凋亡。与体外研究一致，我们还观察到PAN处理大鼠肾皮质中ERRα表达增加与凋亡反应增强一致。这些结果提示ERRα对PAN诱导的MC凋亡和炎症反应具有不利影响，有助于我们更好地理解PAN肾病MC损伤的发病机制。
Glomerular diseases are the leading cause of chronic kidney disease, and mesangial cells (MCs) have been demonstrated to be involved in the pathogenesis. Puromycin aminonucleoside (PAN) is a nephrotoxic drug that induces glomerular injury with elusive mechanisms. The present study was undertaken to investigate the role of PAN in MC apoptosis, as well as the underlying mechanism. Here we found that PAN induced MC apoptosis accompanied by declined cell viability and enhanced inflammatory response. The apoptosis was further evidenced by increments of apoptosis regulator BAX (BAX) and caspase-3 expression. In line with the apoptotic response in MCs following PAN treatment, we also found a remarkable induction of estrogen-related receptor-α (ERRα), an orphan nuclear receptor, at both mRNA and protein levels. Interestingly, ERRα silencing by an siRNA approach resulted in an attenuation of the apoptosis and inflammatory response caused by PAN. More importantly, overexpression of ERRα in MCs significantly triggered MC apoptosis in line with increased BAX and caspase-3 expression. In PAN-treated MCs, ERRα overexpression further aggravated PAN-induced apoptosis. In agreement with the in vitro study, we also observed increased ERRα expression in line with enhanced apoptotic response in renal cortex from PAN-treated rats. These data suggest a detrimental effect of ERRα on PAN-induced MC apoptosis and inflammatory response, which could help us to better understand the pathogenic mechanism of MC injury in PAN nephropathy.