Tubular Glucagon Receptor (GCGR) activation protects against diabetic kidney disease by restoring lysosomal function via V-ATPase.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, imposing a significant global health burden. While SGLT2 inhibitors and GLP-1R agonists offer renoprotection, a substantial unmet need for more effective therapies remains. Recent clinical trials with dual GLP-1R/GCGR agonists like mazdutide and cotadutide suggest a potential kidney benefit from GCGR activation. However, the direct renoprotective role of GCGR and its precise mechanisms within the kidney, particularly in tubular cells, have remained largely uncharacterized, representing a critical gap in understanding DKD pathogenesis.