Ursodeoxycholic acid protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction through acting on ALDH1L2.
Ursodeoxycholic acid protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction through acting on ALDH1L2.
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DOI：
10.1016/j.freeradbiomed.2020.01.182
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发表时间：
2020-01
影响因子：
7.4
通讯作者：
Yunwen Yang;Suwen Liu;Huiping Gao;Peipei Wang;Yue Zhang;A. Zhang;Zhanjun Jia;Songming Huang
中科院分区：
文献类型：
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作者：
Yunwen Yang;Suwen Liu;Huiping Gao;Peipei Wang;Yue Zhang;A. Zhang;Zhanjun Jia;Songming Huang
线粒体功能障碍在急性肾损伤（阿基）中起重要作用。因此，改善线粒体功能的药物可能有益于治疗阿基。熊去氧胆酸（UDCA）已被证明可以预防病理下的线粒体功能障碍，但其在阿基中的作用及其潜在机制仍不清楚。本研究旨在评价UDCA对顺铂诱导的阿基的影响。注射联合或不联合UDCA（60 mg/kg/天）灌胃给药。体外实验中，顺铂联合或不联合UDCA作用于小鼠近端肾小管上皮细胞（mPTC）和人近端肾小管上皮细胞（HK 2）24 h。进行转录组学RNA-seq以分析UDCA的可能靶点。我们的研究结果表明，UDCA沿着降低了顺铂诱导的血清肌酐（Scr）、血尿素氮（BUN）和胱抑素C的升高，并改善了肾小管损伤，表现为肾组织学改善，并阻断了中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和肾损伤分子1（KIM-1）的上调。UDCA对肾小管上皮细胞凋亡的保护作用可能与拮抗线粒体功能障碍和氧化应激有关，其作用靶点是通过RNA-seq分析筛选出的ALDH 1 L2。通过CRISPR/Cas9敲除ALDH 1 L2极大地削弱了UDCA在肾小管细胞中的保护作用。此外，UDCA并没有削弱顺铂在人类癌细胞中的抑制作用。总之，我们的研究结果表明，UDCA通过作用于ALDH 1 L2的表达改善线粒体功能，从而预防顺铂诱导的阿基，表明UDCA治疗阿基的临床潜力。
Mitochondrial dysfunction plays an important role in acute kidney injury (AKI). Thus, the agents improving the mitochondrial function could be beneficial for treating AKI. Ursodeoxycholic acid (UDCA) has been demonstrated to prevent mitochondrial dysfunction under pathology, however, its role in AKI and the underlying mechanism remain unknown. This study aimed to evaluate the effect of UDCA on cisplatin-induced AKI.In vivo, C57BL/6 J mice were treated with cisplatin (25 mg/kg) for 72 h to induce AKI through a single intraperitoneal (i.p.) injection with or without UDCA (60 mg/kg/day) administration by gavage. Renal function, mitochondrial function and oxidative stress were analyzed to evaluate kidney injury.In vitro, mouse proximal tubular cells (mPTCs) and human proximal tubule epithelial cells (HK2) were treated with cisplatin with or without UDCA treatment for 24 h. Transcriptomic RNA-seq was preformed to analyze possible targets of UDCA. Our results showed that cisplatin-induced increments of serum creatinine (Scr), blood urea nitrogen (BUN), and cystatin C were significantly reduced by UDCA along with ameliorated renal tubular injury evidenced by improved renal histology and blocked upregulation of neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1). Meanwhile, the apoptosis induced by cisplatin was also markedly attenuated by UDCA administration.In vitro, UDCA treatment protected against tubular cell apoptosis possibly through antagonizing mitochondrial dysfunction and oxidative stress by targeting ALDH1L2 which was screened out by an RNA-seq analysis. Knockout of ALDH1L2 by CRISPR/Cas9 greatly blunted the protective effects of UDCA in renal tubular cells. Moreover, UDCA did not diminish cisplatin's antineoplastic effect in human cancer cells. In all, our results demonstrated that UDCA protects against cisplatin-induced AKI through improving mitochondrial function through acting on the expression of ALDH1L2, suggesting a clinical potential of UDCA for the treatment of AKI.