E2F7 and E2F8 attenuate diabetic kidney disease by suppressing E2F1-induced tubular senescence

Targeting cellular senescence represents a critical frontier for mitigating diabetic kidney disease (DKD), yet the transcriptional hierarchies governing renal senescence remain incompletely defined. While the E2F family is pivotal in cell cycle regulation, its specific contribution to the senescent phenotype in DKD is unclear. Here we show that resveratrol attenuates renal fibrosis and cellular senescence in db/db mice by modulating the interaction between activator and repressor E2f transcription factors. We demonstrate that hyperglycemic conditions drive the upregulation of E2f1 in mouse renal tubular epithelial cells, directly precipitating DNA damage and senescence. Accordingly, in vivo knockdown of E2f1 significantly ameliorates DKD pathology. Mechanistically, resveratrol induces the expression of the atypical repressors E2f7 and E2f8. These repressors directly bind to the E2F1 promoter region to repress its transcription, thereby abrogating E2f1-mediated cellular senescence. These findings elucidate a transcriptional axis linking resveratrol to the suppression of renal senescence and highlight the E2F1-E2F7/8 regulatory loop as a promising therapeutic target.