Proximal tubular EZH2 inhibits diabetic kidney disease by suppressing SHC1-mediated oxidative stress

Diabetic kidney disease (DKD) represents one of the most severe complications of diabetes. Although EZH2 (Enhancer of Zeste Homolog 2) has been implicated in renal injury and diabetes, its specific function within renal tubular cells in DKD remains unclear. Here, we explored the role and downstream mechanism of tubular EZH2 in DKD progression. Renal EZH2 expression was significantly upregulated in DKD. Single-nucleus RNA sequencing and immunofluorescence analyses verified that such elevation was restricted to proximal tubular epithelial cells. Conversely, tubular-specific deletion of Ezh2 exacerbated renal dysfunction and fibrosis in DKD mice. In vitro gain- and loss-of-function experiments in high glucose-stimulated HK2 cells further validated that EZH2 plays a renoprotective role under diabetic conditions. Mechanistically, we demonstrated that EZH2 epigenetically suppresses the pro-oxidative mediator SHC1. In the DKD mouse model, renal SHC1 protein abundance was markedly increased upon tubular Ezh2 knockout, accompanied by reduced levels of antioxidant enzymes SOD1 and SOD2, significantly elevated MDA, and depleted GSH. Consistent with these in vivo observations, in vitro functional assays further validated that EZH2 epigenetically downregulates SHC1 and alleviates such oxidative stress perturbations. Finally, we verified that SHC1 inhibition rescues the exacerbated fibrotic response and oxidative damage triggered by pharmacological EZH2 suppression under high-glucose conditions. In conclusion, tubular EZH2 protects against DKD via inhibiting SHC1-driven oxidative stress.