This study explores the roles of Mettl3-induced N6-methyladenosine (m6A) modifications in Focal segmental glomerulosclerosis (FSGS). The findings reveal that inhibition of Mettl3 results in podocyte injury by modulating the TJP1CDC42 pathway. Moreover, Administration of N6-methyladenosine attenuates the FSGS phenotype in WT mice induced by Adriamycin and Mettl3 deficiency.
Abstract
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.
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