Acarbose ameliorates podocyte injury and glomerular lesions in diabetic nephropathy through USP46 activation

The ubiquitin-proteasome system (UPS) is important for podocyte health, but the specific UPS proteins involved in podocyte injury of diabetic nephropathy (DN) are not well known. Patients with DN have lower expression of USP46 in podocytes, which is linked to higher proteinuria. Deleting the Usp46 gene in podocytes of mice (Usp46^PKO mice) led to spontaneous albuminuria and worsened podocyte injury and glomerular lesions under diabetic conditions. Mechanically, loss of USP46 caused cytosolic translocation and aggregation of TAR DNA binding protein 43 (TDP-43) in podocytes. Here, we identified acarbose as an agonist of USP46. Treatment with acarbose reduced TDP-43 aggregation in podocytes, prevented podocyte loss, and mitigated albuminuria in diabetic mice; the therapeutic efficacy of acarbose was abolished in Usp46^PKO mice. This research elucidates the role of USP46 in podocyte homeostasis and injury in DN and indicates a potential therapeutic impact for acarbose in DN beyond the regulation of blood glucose concentrations through its activation of USP46.