KIDNEY fibrosis in ageing is driven by epigenetic silencing of fibroblast growth factor receptor 2 (FGFR2), according to new research identifying a potential therapeutic target for chronic kidney disease (CKD).
Age-related kidney decline remains a major contributor to CKD, with kidney fibrosis a central pathological hallmark. However, the biological mechanisms linking ageing to progressive renal scarring have remained unclear. New findings shed light on how epigenetic changes, specifically DNA hypermethylation, may directly drive this process.
Kidney Fibrosis and Ageing: A Growing Burden
Kidney fibrosis, characterised by excessive extracellular matrix deposition and tissue scarring, leads to irreversible loss of renal function. As populations age, the burden of CKD continues to rise, making it critical to understand the molecular drivers of kidney fibrosis. Ageing kidneys are known to exhibit tubular atrophy, persistent injury, and increased cellular senescence, but the regulatory mechanisms behind these changes have been poorly defined.
FGFR2 Hypermethylation Identified as Key Driver
Using a natural ageing mouse model, researchers integrated transcriptomic and DNA methylation analyses to explore these mechanisms. They observed a global increase in DNA methylation with age, alongside significant structural kidney damage and elevated markers of senescence and injury.
Notably, FGFR2 emerged as a key target of age-associated hypermethylation. This epigenetic modification suppressed FGFR2 expression, particularly in renal tubular cells. Multiple validation techniques confirmed consistent downregulation of FGFR2 in ageing kidney tissue.
Functional Impact on Kidney Fibrosis Progression
Functional experiments revealed that inhibiting FGFR2 accelerated cellular senescence and increased fibrosis-related markers in vitro. These findings suggest that loss of FGFR2 activity plays a causal role in promoting kidney fibrosis.
In addition, reduced co-localisation between FGFR2 and fibroblast growth factor 23 (FGF23) indicated disruption of a key signalling pathway, further contributing to renal dysfunction and fibrotic remodelling.
Implications for Future CKD Therapies
These findings highlight FGFR2 as a promising therapeutic target for mitigating kidney fibrosis and slowing age-related renal decline.
However, the study was conducted in animal models, and further research is needed to confirm these mechanisms in humans and to explore potential interventions targeting DNA methylation.
If validated clinically, strategies aimed at reversing FGFR2 hypermethylation could represent a novel approach to treating kidney fibrosis and improving outcomes in CKD.
Reference
Qian Y et al. DNA hypermethylation of FGFR2 drives fibrosis in the aging kidney. Sci Rep. 2026;DOI:10.1038/s41598-026-51208-4.
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