Focal segmental glomerulosclerosis (FSGS) is a common glomerular lesion characterized by primary podocyte injury. Multiple genetic risk factors have been reported to be associated with the occurrence of FSGS. However, whether epigenetic factors, particularly N6-methyladenosine (m6A) modification, are involved in the pathogenesis of FSGS remains unclear.
Recently, researchers published an article titled "Mettl3-Mediated m6A Modification Represents a Novel Therapeutic Target for FSGS" in Advanced Science. The study constructed a podocyte-specific N⁶-adenosine methyltransferase-like protein 3 (Mettl3) knockout mouse model (Mettl3podko mice) and isolated podocytes from the mice for RNA-seq analysis. Results showed that RNA m⁶A methylation levels were significantly reduced in both FSGS animal models and human glomerular tissues. Mettl3podko mice also exhibited significantly decreased podocyte RNA m⁶A levels and displayed FSGS-related phenotypes.
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RNA-seq and m6A-immunoprecipitation RNA sequencing revealed that silencing Mettl3 expression in podocytes led to gene expression profiles associated with slit diaphragm dysfunction. RNA immunoprecipitation assays and hybridization chain reaction (HCR) analysis further identified the slit diaphragm marker TJP1 as a potential target of Mettl3. Loss-of-function and gain-of-function analyses demonstrated that Mettl3 enhances podocyte RNA m6A modification, potentially through the TJP1–CDC42 pathway. Finally, intervention with m⁶A-mimicking compounds in both Mettl3podko mice and adriamycin (ADR)-induced FSGS mice significantly delayed disease progression. Therefore, these studies confirm that Mettl3-mediated RNA m⁶A modification is crucial for maintaining podocyte structure and function, and this modification pathway also holds promise as a potential therapeutic target for FSGS.
Figure 1. Administration of N6-methyladeine ameliorates the progression of FSGS in ADR-induced FSGS mice. (Zhu F, et al., 2025)
Focal segmental glomerulosclerosis (FSGS) is a histopathological lesion characterized by varying degrees of podocyte and foot process effacement and capillary lumen obliteration. The disease primarily originates from direct podocyte damage and is the type most likely to progress to end-stage renal disease (ESRD) among primary nephrotic syndromes. FSGS can occur at any age and has diverse etiologies. However, due to the unclear pathogenesis, there are currently no specific treatments for FSGS.
Podocytes are terminally differentiated cells that play a critical role in the glomerular filtration barrier through their foot processes. Podocyte foot processes form complex interdigitating structures with adjacent podocyte foot processes. Multiple interdigitating foot processes are connected by slit diaphragms; the slit diaphragm spans the glomerular basement membrane (GBM) surface, constituting the final barrier of filtration. Dysfunction of podocyte-specific genes can disrupt the glomerular basement membrane structure, leading to foot process fusion and podocyte detachment.
Previous studies have confirmed that multiple genes specifically expressed in podocytes are associated with FSGS. Mutations in these genes disrupt the integrity of the slit diaphragm complex, subsequently causing proteinuria, which is the hallmark symptom of FSGS. Additionally, nuclear transcription factors are crucial for podocyte development and functional maintenance. Related research indicates that mutations in these transcription factors are also associated with the pathogenesis of focal segmental glomerulosclerosis.
RNA has over 100 modification types, among which N⁶-methyladenosine (m⁶A) methylation modification is the most common, abundant, and evolutionarily conserved modification in eukaryotic messenger RNA (mRNA). m⁶A methylation modification is a key factor in the post-transcriptional regulation of mRNA splicing, translation, and degradation processes. This modification process is catalyzed by methyltransferases and can be reversed by demethylases. m⁶A methylation modification participates in various biological processes.
Recent studies have shown that Mettl3-mediated m⁶A methylation modification is associated with the pathogenesis of polycystic kidney disease and diabetic nephropathy (DN). Other research has indicated that m⁶A modification levels are significantly elevated in patients with FSGS and diabetic nephropathy, and Mettl14 expression levels show an upward trend in corresponding animal models. However, to date, the role and specific mechanisms of m⁶A modification in kidney diseases such as focal segmental glomerulosclerosis still require further elucidation.
Reference
Zhu F, et al. Mettl3‐Mediated m6A Modification Represents a Novel Therapeutic Target for FSGS. Advanced Science, 2025: e01242.