DNA hypermethylation of FGFR2 drives fibrosis in the aging kidney

Kidney fibrosis is a central pathological feature driving progressive functional decline in chronic kidney disease (CKD); however, the molecular and epigenetic mechanisms linking kidney fibrosis to aging remain incompletely understood. In this study, we employed a natural aging mouse model and integrated transcriptomic and DNA methylation analyses to delineate age-associated kidney degenerative features and to identify key genes involved in this process. Our results showed that aging kidneys exhibited pronounced interstitial fibrosis and tubular atrophy, accompanied by increased expression of senescence markers, senescence-associated secretory phenotype (SASP) factors, and kidney injury molecule-1 (KIM-1), indicating persistent kidney injury during aging. Reduced representation bisulfite sequencing (RRBS) revealed a global, age-dependent increase in DNA methylation levels. Integrative methylome-transcriptome analyses identified fibroblast growth factor receptor 2 (FGFR2) as a prominent target of age-associated hypermethylation. Multilevel validation using RT-qPCR, Western blotting, immunofluorescence co-localization, and pyrosequencing consistently confirmed that FGFR2 expression was significantly reduced in aging kidney tissue, particularly in kidney tubular regions. Functional studies demonstrated that pharmacological inhibition of FGFR2 in vitro accelerated cellular senescence and upregulated fibrosis-related markers, supporting a causal role for FGFR2 loss in promoting kidney aging. Furthermore, reduced FGFR2 expression was accompanied by decreased co-localization with fibroblast growth factor 23 (FGF23) in aging kidneys, suggesting potential impairment of the FGF23/FGFR2 signaling axis. Collectively, these findings suggest that epigenetic silencing of FGFR2 contributes to kidney senescence and fibrotic remodeling during kidney aging and highlight FGFR2 as a potential therapeutic target for mitigating age-related kidney decline.