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MiR-449a downregulation alleviates the progression of renal interstitial fibrosis by mediating the KLF4/MFN2 axis
Xiang-Dong Fang1, Jia-Ke He2, Yan-Xia Chen1
1Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi Province, China.
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.
Insights
Downregulation of microRNA-449a (miR-449a) alleviates renal interstitial fibrosis (RIF) by targeting KLF4 and regulating MFN2. This suggests miR-449a is a potential therapeutic target for RIF.
Area of Science:
- Molecular Biology
- Renal Pathophysiology
- MicroRNA Therapeutics
Background:
- Renal interstitial fibrosis (RIF) poses a significant health risk.
- MicroRNAs (miRNAs) are implicated in fibrotic disease progression.
- The specific role of miR-449a in RIF remains largely uncharacterized.
Purpose of the Study:
- To investigate the function of miR-449a in the development of RIF.
- To elucidate the molecular mechanisms underlying miR-449a's role in RIF.
- To explore the therapeutic potential of targeting miR-449a for RIF treatment.
Main Methods:
- Established in vitro and in vivo models of RIF.
- Utilized dual-luciferase reporter and chromatin immunoprecipitation assays to determine molecular interactions.
- Assessed pathological changes and gene/protein expression via Masson staining, qPCR, and Western blot.
Main Results:
- Transforming growth factor-beta 1 (TGF-β1) modulated miR-449a, KLF4, and MFN2 expression.
- miR-449a directly targeted KLF4, and KLF4 regulated MFN2 transcription.
- Downregulation of miR-449a ameliorated TGF-β1-induced fibrosis in vitro and RIF symptoms in vivo.
Conclusions:
- miR-449a downregulation attenuates RIF development through the KLF4/MFN2 axis.
- The miR-449a/KLF4/MFN2 pathway represents a novel mechanism in RIF.
- miR-449a emerges as a potential therapeutic target for treating RIF.
