<i>Mettl3</i> ‐Mediated m6A Modification Represents a Novel Therapeutic Target for FSGS

Focal segmental glomerulosclerosis (FSGS) is a common glomerular lesion that manifests as a primary podocyte injury. Multiple genetic risk factors have been reported to be associated with the development of FSGS. However, whether epigenetic factors, especially N6-methyladenosine (m6A) modifications, are involved in the pathogenesis of FSGS remains unclear. By generating a mouse line with a specific deletion of N6-adenosine-methyltransferase-like 3 (Mettl3) in podocytes (Mettl3^podkomice), podocytes are isolated and performed RNA-seq. It is shown that RNA m6A methylation levels are reduced in the renal glomeruli of both animal models and patients with FSGS. A significant decrease in RNA m6A levels in podocytes and the development of an FSGS phenotype are observed in the Mettl3^podko mice. Furthermore, RNA-seq and m6A-immunoprecipitated RNA sequencing revealed that silencing Mettl3 expression in podocytes led to a gene expression profile associated with slit diaphragm dysfunction. RNA immunoprecipitation assay and hybridization chain reaction (HCR) analysis further identified the slit diaphragm marker TJP1 as a potential target of Mettl3. Moreover, loss- and gain-of-function analyses showed that Mettl3 enhances podocyte RNA m6A modification, probably through the TJP1-CDC42 pathway. Finally, treatment of Mettl3^podko and adriamycin (ADR)-induced FSGS mice with m6A-mimic compounds markedly ameliorated the progression of FSGS. The findings demonstrate that Mettl3-mediated RNA m6A modification is essential for maintaining podocyte architecture and function and represents a potential therapeutic target for FSGS.