Ursodeoxycholic acid protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction through acting on ALDH1L2.

Abstract

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.

• Authors: Yunwen Yang, Suwen Liu, Huiping Gao, Peipei Wang, Yue Zhang, Aihua Zhang, Zhanjun Jia, Songming Huang
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 152 Pg. 821-837 (05 20 2020) ISSN: 1873-4596 [Electronic] United States
• PMID: 32004633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Ursodeoxycholic Acid
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, drug therapy, genetics)
• Animals
• Apoptosis
• Cisplatin (toxicity)
• Kidney (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria
• Ursodeoxycholic Acid (metabolism, pharmacology)