Glucagon-Like Peptide-1 and its Cleavage Products are Renoprotective in Murine Diabetic Nephropathy

Incretin based therapies, including GLP-1 receptor agonists and dipeptidylpeptidase 4 (DPP-4) inhibitors, are potent glucose lowering drugs. Still, only GLP-1 receptor agonists with close peptide homology to GLP-1 (liraglutide and semaglutide) but neither exenatide based GLP-1 receptor agonists nor DPP-4 inhibitors were found to reduce cardiovascular events. This different response might relate to GLP-1 receptor independent actions of GLP-1 caused by cleavage products only liberated by GLP-1 receptor agonists with close peptide structure to GLP-1. To test this hypothesis we directly compared metabolic, renal and cardiac effects of GLP-1 and its cleavage products in diabetic db/db mice. Using an adeno-associated viral vector system we overexpressed DPP-4 resistant GLP-1(7-37Mut8) and the two GLP-1 cleavage products, GLP-1(9-37) and GLP-1(28-37) in diabetic db/db mice. Only GLP-1(7-37Mut8), but none of the cleavage products significantly improved glucose metabolism. Still, all GLP-1 constructs significantly reduced tubulointerstitial renal damage, lowered expression of the tubular injury markers and attenuated renal accumulation of macrophages and T cells. This was associated with a systemic immunomodulatory effect, which was similarly found in an acute renal ischemia/reperfusion injury model. In conclusion , GLP-1 cleavage products proved sufficient to mediate organ protective effects, which might help to explain differences between GLP-1 receptor agonists.