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Identification and Validation of miR-206-3p Targeting WT-1 Promotes Membranous Nephropathy Through a Comprehensive
Xiaowan Wang1,2,3,4, Fangqiang Zhou1,2, Chunmei Fu1,2
1State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
Abstract:
Membranous nephropathy (MN), a major cause of end-stage renal disease, has limited therapeutics due to unclear targets. MicroRNAs (miRs) play critical roles in various diseases, but their role in MN remains unknown. This study utilizes a series of public databases, bioinformatics tools, and validation methods to identify key miRs and molecular mechanisms involved in MN. The GEO, miRbase, and TargetScan databases, along with the R package, Bioinformatics and ImageGP platform, were utilized to identify biomarkers in MN. 13 upregulated differentially expressed miRs (DEmiRs) were found across datasets. Weighted gene co-expression network analysis (WGCNA) showed that 58 miRs were strongly positively correlated with MN. Among these, 11 overlapping miRs were analyzed using the least absolute shrinkage and selection operator (LASSO) method to identify 5 candidate hub miRs. A series of approaches, including target gene prediction, disease-related analysis, and machine learning, brought miR-206 and WT-1 into focus as biomarkers for MN. Then, the passive Heymann nephropathy rat model and the adriamycin-injured podocytes were developed to validate these analyses and explore potential mechanisms. The gene or protein expression of upregulated miR-206-3p and downregulated WT-1 was verified in apoptotic podocytes both in vivo and in vitro. Moreover, the C-MIP/Nephrin/PI3K pathway appeared to be the potential mechanism through which miR-206-3p targets WT-1 to mediate podocyte apoptosis in MN. Ultimately, inhibition of miR-206-3p restored WT-1 expression and attenuated podocyte apoptosis. In summary, this study sheds light on the role of miR-206-3p targeting WT-1 in MN and confirms its involvement in podocyte apoptosis via the C-MIP/Nephrin/PI3K pathway.
Insights
MicroRNAs (miRs) are implicated in membranous nephropathy (MN). This study identifies miR-206 as a key player targeting WT-1, offering potential therapeutic strategies for MN by inhibiting podocyte apoptosis.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Membranous nephropathy (MN) is a leading cause of kidney failure with limited treatment options.
- The role of microRNAs (miRs) in MN pathogenesis is largely unknown.
- Identifying novel molecular targets is crucial for developing effective MN therapies.
Purpose of the Study:
- To identify key microRNAs (miRs) and molecular mechanisms involved in membranous nephropathy (MN).
- To investigate the role of specific miRs and their target genes in podocyte apoptosis.
- To explore potential therapeutic targets for MN.
Main Methods:
- Utilized public databases (GEO, miRbase, TargetScan) and bioinformatics tools (WGCNA, LASSO).
- Employed machine learning and disease-related analyses to identify biomarkers.
- Validated findings in a rat model of nephropathy and in vitro podocyte injury models.
Main Results:
- Identified 13 upregulated differentially expressed miRs (DEmiRs) and 58 positively correlated miRs in MN.
- Pinpointed miR-206 and WT-1 as key biomarkers for MN.
- Confirmed upregulation of miR-206-3p and downregulation of WT-1 in apoptotic podocytes.
- Elucidated the C-MIP/Nephrin/PI3K pathway as the mechanism for miR-206-3p targeting WT-1.
- Demonstrated that inhibiting miR-206-3p restores WT-1 expression and reduces podocyte apoptosis.
Conclusions:
- miR-206-3p plays a critical role in mediating podocyte apoptosis in membranous nephropathy (MN) by targeting WT-1.
- The C-MIP/Nephrin/PI3K pathway is involved in the miR-206-3p/WT-1 interaction.
- Inhibition of miR-206-3p represents a potential therapeutic strategy for MN.
