MOV10-mediated alternative splicing regulates mesangial cell proliferation in diabetic kidney disease.

BACKGROUND

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, characterized by abnormal mesangial cell (MC) proliferation, yet the underlying mechanisms remain unclear.

METHODS

Using RNA-seq and qRT-PCR, Mov10 was identified as the most highly expressed splicing factor (SF) in high-glucose MCs among seven candidates (Mov10, Ssb, Rbm25, Fastk, Dek, Nsrp1, Cwc15). Functional assays (EdU, CCK-8) assessed MC proliferation, while qRT-PCR and Western blot measured inflammatory and fibrotic markers. RIP-seq, RNA-seq, and bioinformatics analyses were used to identify MOV10-binding sites, target genes, pathways, and alternative splicing (AS) events.

RESULTS

Transcriptome analysis revealed extensive AS in DKD, with exon skipping being the most frequent. MOV10 knockdown suppressed MC proliferation and reduced inflammation and fibrosis, whereas MOV10 overexpression had opposite effects. RIP-seq showed MOV10 preferentially bound the ACGACG motif within CDS regions. MOV10 regulated AS of proliferation-related genes, including Tead1, Dcbld2, Slc9a5, Akap13, Tfdp2, and Trp53bp1, primarily via exon skipping.

CONCLUSIONS

This study identifies MOV10 as a novel DKD-associated splicing factor. By modulating AS of proliferation-related genes, MOV10 promotes mesangial proliferation, inflammation, and fibrosis, highlighting a potential therapeutic target in DKD.