DKK3, regulated by FOXF1-EZH2 axis, takes action on tubular epithelial cells senescence to trigger glomerular endothelial cells ferroptosis involving in renal fibrosis

Abstract

Chronic kidney disease (CKD) can be accelerated by renal fibrosis. Dickkopf-3 (DKK3) plays a role in regulating renal fibrosis, while tubular cell senescence contributes to fibrosis development. Here, the role and mechanism of DKK3 on senescence and renal fibrosis were evaluated. We demonstrated that in CKD patients and Unilateral Ureteral Obstruction (UUO) mice, downregulation of FOXF1 and upregulation of DDK3 was observed, of which expression patterns exhibited negative association. Reinforced FOXF1 protected against H₂O₂-triggered tubular cell damage, fibrosis, and senescence, which was reversed by DKK3 overexpression. In UUO mice, FOXF1 depletion worsened renal fibrosis and senescence. Mechanistically, FOXF1 was identified to be a transcriptional activator of EZH2 to mediated epigenetic silence of DKK3 via H3K27me3 levels. Moreover, exosomal DKK3 from tubular cells controlled Endothelial to Mesenchymal Transition, oxidative stress and ferroptosis in MRGECs. Overall, our data reveal that the FOXF1-EZH2-DKK3 axis controls tubular cell senescence. Exosome-borne DKK3 influences lipid peroxidation in glomerular endothelial cells, inducing ferroptosis and advancing renal fibrosis, which provides new therapeutic targets for CKD treatment.