MicroRNA-34a Promotes Renal Fibrosis by Downregulation of Klotho in Tubular Epithelial Cells

• Published in: Molecular therapy Vol. 27; no. 5; pp. 1051 - 1065
• Main Authors: Liu, Yong, Bi, Xianjin, Xiong, Jiachuan, Han, Wenhao, Xiao, Tangli, Xu, Xinli, Yang, Ke, Liu, Chi, Jiang, Wei, He, Ting, Yu, Yanlin, Li, Yan, Zhang, Jingbo, Zhang, Bo, Zhao, Jinghong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.05.2019; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: 3' Untranslated regions; Animals; Apoptosis; Biopsy; Cell cycle; Cell Line; Diabetes; dihydromyricetin; Disease Models, Animal; Doxorubicin - toxicity; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelial-Mesenchymal Transition - drug effects; Experiments; Fibrosis; Fibrosis - chemically induced; Fibrosis - drug therapy; Fibrosis - genetics; Fibrosis - pathology; Flavonols - pharmacology; Gene expression; Glucuronidase - antagonists & inhibitors; Glucuronidase - genetics; Humans; Kidney - drug effects; Kidney - pathology; Kidney diseases; Kidney Diseases - chemically induced; Kidney Diseases - drug therapy; Kidney Diseases - genetics; Kidney Diseases - pathology; Kidney Tubules - metabolism; Kidney Tubules - pathology; Kidneys; Klotho; Klotho protein; Mesenchyme; Mice; microRNA-34a; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; miRNA; Nephropathy; Original; p53 Protein; Pathogenesis; R&D; renal fibrosis; Research & development; Signal Transduction - drug effects; Statistical analysis; Surgery; TGF-β1; Transforming Growth Factor beta1 - genetics; Transforming growth factor-b1; Ureteral Obstruction - chemically induced; Ureteral Obstruction - drug therapy; Ureteral Obstruction - genetics; Ureteral Obstruction - pathology; Urine; United States > US; China; microRNA-34a; TGF-β1; renal fibrosis; Klotho; dihydromyricetin
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.02.009

Renal fibrosis is the main pathological characteristic of chronic kidney disease (CKD), whereas the underlying mechanisms of renal fibrosis are not clear yet. Herein, we found an increased expression of microRNA-34a (miR-34a) in renal tubular epithelial cells of patients with renal fibrosis and mice undergoing unilateral ureteral obstruction (UUO). In miR-34a−/− mice, miR-34a deficiency attenuated the progression of renal fibrosis following UUO surgery. The miR-34a overexpression promoted epithelial-to-mesenchymal transition (EMT) in cultured human renal tubular epithelial HK-2 cells, which was accompanied by sharp downregulation of Klotho, an endogenous inhibitor of renal fibrosis. Luciferase reporter assay revealed that miR-34a downregulated Klotho expression though direct binding with the 3′ UTR of Klotho. Conversely, overexpression of Klotho prevented miR-34a-induced EMT in HK-2 cells. Furthermore, results showed that miR-34a was induced by transforming growth factor β1 (TGF-β1) through p53 activation, whereas dihydromyricetin could inhibit TGF-β1-induced miR-34a overexpression. Accordingly, dihydromyricetin administration dramatically restored the aberrant upregulation of miR-34a and Klotho reduction in obstructed kidney, and markedly ameliorated renal fibrosis in the Adriamycin nephropathy and UUO model mice. These findings suggested that miR-34a plays an important role in the progression of renal fibrosis, which provides new insights into the pathogenesis and treatment of CKD. [Display omitted] The pathogenesis of renal fibrosis is poorly understood, and more effective therapies against renal fibrosis are urgently needed. In this issue of Molecular Therapy, Liu et al. (2019) show that miR-34a promotes renal fibrosis by downregulation of Klotho. Dihydromyricetin displays a strong ability to inhibit the progression of renal fibrosis in CKD mice by rescuing miR-34a-mediated Klotho reduction.