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. 2023 Jul;55(7):1837-1846.
doi: 10.1007/s11255-023-03503-6. Epub 2023 Feb 12.

MiR-449a downregulation alleviates the progression of renal interstitial fibrosis by mediating the KLF4/MFN2 axis

Xiang-Dong Fang  1 , Jia-Ke He  2 , Yan-Xia Chen  1 , Ben Ke  1 , Shu-Ying Zhu  1 , Chu-Qiao Fan  1 , Wei-Ping Tu  3 , Ping Li  4
Affiliations

MiR-449a downregulation alleviates the progression of renal interstitial fibrosis by mediating the KLF4/MFN2 axis

Xiang-Dong Fang et al. Int Urol Nephrol. 2023 Jul.

Abstract

Background: Renal interstitial fibrosis (RIF) seriously threatens the health of individuals. MiRNAs regulate the progression of fibrosis. Nevertheless, the detailed function of miR-449a in RIF is largely unknown.

Methods: In vitro and in vivo models of RIF were developed to evaluate the function of miR-449a. The relationship among miR-449a, KLF4, and MFN2 was explored using a dual-luciferase reporter assay and chromatin immunoprecipitation. Additionally, the pathological changes in the mice were detected using Masson staining. The mRNA and protein expressions were assessed using quantitative reverse transcription polymerase chain reaction and western blot, respectively.

Results: TGF-β1 downregulated the expressions of KLF4 and MFN2 in TCMK-1 cells, but upregulated the level of miR-449a. The downregulation of miR-449a significantly inhibited TGF-β1-induced upregulation of fibrotic proteins in TCMK-1 cells. Meanwhile, miR-449a directly targeted KLF4. Moreover, KLF4 overexpression activated MFN2 transcription and reversed TGF-β1-induced fibrosis by positively regulating MFN2. Furthermore, the downregulation of miR-449a could obviously alleviate the symptoms of RIF in mice with unilateral ureteral obstruction.

Conclusion: MiR-449a downregulation attenuated the development of RIF by mediating the KLF4/MFN2 axis. Therefore, miR-449a might act as a target in treating RIF.

Keywords: KLF4; MFN2; Renal interstitial fibrosis; miR-449a.

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