Estrogen-related receptor α is essential for maintaining mitochondrial integrity in cisplatin-induced acute kidney injury
Estrogen-related receptor α is essential for maintaining mitochondrial integrity in cisplatin-induced acute kidney injury
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DOI：
10.1016/j.bbrc.2018.03.080
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发表时间：
2018-04-15
影响因子：
3.1
通讯作者：
Wada，Jun
中科院分区：
文献类型：
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作者：
Tsushida，Keigo;Tanabe，Katsuyuki;Wada，Jun
急性肾损伤(AKI)不仅与较高的住院死亡率有关，而且与随后发生的慢性肾脏疾病(CKD)有关。最近的证据表明，线粒体功能障碍和动力学受损参与了AKI的发病机制。雌激素相关受体α(ERRα)是一种孤儿核受体，作为转录因子调节线粒体生物发生和氧化磷酸化所需基因的转录。在本研究中，我们研究了ERRα缺乏对顺铂诱导的急性心肌梗死进展的影响。雄性C57BL/6 J野生型和ERRα−/-小鼠一次性腹腔注射顺铂20 mg/kg。注射后72小时检测肾功能和肾组织形态。ERRα在肾小管中有表达，顺铂抑制其向胞核的移位。ERRα缺乏加重了顺铂诱导的肾功能障碍和肾小管损伤，以及氧化应激和细胞凋亡。ERRα−/-小鼠肾脏线粒体DNA含量降低，线粒体肿胀，嵴减少。此外，这些小鼠线粒体融合蛋白mitofusin-2的表达较低。顺铂诱导的线粒体DNA减少和线粒体结构改变在ERRα−/-小鼠中更为严重。在培养的小鼠近端肾小管上皮细胞中，ERRα反向激动剂XCT-790显著抑制丝裂原-2的表达并诱导线粒体断裂。综上所述，我们的发现提示ERRα可能通过受损的线粒体动力学参与顺铂诱导的急性心肌梗死的进展。
Acute kidney injury (AKI) has been associated with not only higher in-hospital mortality but also the subsequent development of chronic kidney disease (CKD). Recent evidence has suggested the involvement of mitochondrial dysfunction and impaired dynamics in the pathogenesis of AKI. Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that acts as a transcription factor to regulate the transcription of genes required for mitochondrial biogenesis and oxidative phosphorylation. In the present study, we examined the effects of ERRα deficiency on the progression of AKI induced by cisplatin. Male C57BL/6 J wild-type and ERRα−/-mice received a single intraperitoneal injection of 20 mg/kg cisplatin. Seventy-two hours after the injection, kidney function and morphology were evaluated. ERRα expression was observed in renal tubules, and cisplatin inhibited its translocation into nuclei. ERRα deficiency exacerbated cisplatin-induced renal dysfunction and tubular injury, as well as oxidative stress and apoptosis. ERRα−/-mice kidneys revealed lower mitochondrial DNA content and swollen mitochondria with reduced cristae. In addition, these mice had lower expression of the mitochondrial fusion protein mitofusin-2. The cisplatin-induced decrease in mitochondrial DNA and altered mitochondrial structure were more severe in ERRα−/-mice. In cultured mouse proximal tubular epithelial cells, the ERRα inverse agonist XCT-790 significantly inhibited mitofusin-2 expression and induced mitochondrial fragmentation. Taken together, our findings suggest the involvement of ERRα in the progression of cisplatin-induced AKI probably through impaired mitochondrial dynamics.