USP25 ameliorates diabetic nephropathy by inhibiting TRAF6-mediated inflammatory responses

•Knockout of USP25 exacerbates diabetic kidney disease accompanied with increased renal inflammation.•USP25 inhibits inflammatory responses induced by advanced glycation end-products.•USP25 attenuates NF-κB and MAPK activation by reducing K63 polyubiquitination of TRAF6. Diabetic kidney disease (DKD) is a common diabetic vascular complication affecting nearly 40% of patients with diabetes. The lack of efficacious therapy for DKD necessitates the in-depth investigation of the molecular mechanisms underlying the pathogenesis and progression of DKD, which remain incompletely understood. Here, we discovered that the expression of USP25, a deubiquitinating enzyme, was significantly upregulated in the kidney of diabetic mice. Ablation of USP25 had no influence on glycemic control in type 1 diabetes but significantly aggravated diabetes-induced renal dysfunction and fibrosis by exacerbating inflammation in the kidney. In DKD, USP25 was mainly expressed in glomerular mesangial cells and kidney-infiltrating macrophages. Upon stimulation with advanced glycation end-products (AGEs), USP25 markedly inhibited the production of proinflammatory cytokines in these two cell populations by downregulating AGEs-induced activation of NF-κB and MAPK pathways. Mechanistically, USP25 interacted with TRAF6 and inhibited its K63 polyubiquitination induced by AGEs. Collectively, these findings identify USP25 as a novel regulator of DKD.