Renoprotective effects of tubular glucagon receptor activation mediated by V-ATPase.

Recent clinical trials have shown that dual GLP-1R/GCGR agonists, including mazdutide and cotadutide, provide kidney benefits in patients with type 2 diabetes and CKD, suggesting a potential contribution of GCGR activation to these renal effects. However, whether GCGR directly confers renoprotection and the underlying mechanisms remain unclear. Here, using tubule-specific GCGR loss- and gain-of-function mouse models and human kidney samples, we show that tubular GCGR signaling exerts an important renoprotective role in DKD. Tubular GCGR expression is reduced in humans and mice with DKD and correlates with worse kidney function and increased renal injury. Genetic ablation of tubular GCGR markedly exacerbates DKD and induces pronounced phospholipid accumulation within enlarged lysosomes. Mechanistically, GCGR loss disrupts its association with the V-ATPase V1A subunit ATP6V1A, compromises V1-V0 assembly, and thereby impairs lysosomal acidification. This defect leads to impaired phospholipid hydrolysis and protease maturation, blockade of autophagic flux, and ultimately tubular cell injury. In vivo, ATP6V1A overexpression markedly reverses GCGR deficiency-induced lysosomal dysfunction and DKD progression. Consistently, re-expression of tubular GCGR via AAV9 restores lysosomal function, reduces phospholipid accumulation, and mitigates renal injury in DKD. Together, these findings provide genetic evidence for the renoprotective role of tubular GCGR in DKD, delineate a kidney-intrinsic GCGR-ATP6V1A-lysosome axis that protects tubular integrity, and extend prior GCGR-in-kidney observations into a more concrete GCGR-lysosome mechanism.