Comparative effects of semaglutide tirzepatide and retatrutide on renal fibrosis in UUO and aged mice.

Chronic kidney disease is a major health burden. Given the therapeutic potential of GLP-1 receptor agonists (semaglutide, tirzepatide, and retatrutide) in diabetic nephropathy, we evaluated their anti-fibrotic and anti-inflammatory effects in non-diabetic renal fibrosis using HK-2 cells and murine UUO and aging models. Integrating in vivo and in vitro data showed model- and drug-specific patterns of action among the three agents. In the UUO model, semaglutide effects were associated with PI3K-AKT inhibition, tirzepatide effects with PI3K-AKT inhibition and PPAR pathway activation, and retatrutide effects with concurrent inhibition of both PI3K-AKT and NF-κB pathways. In the aging model, all three drugs were linked to G2/M arrest mitigation. Retatrutide showed the greatest efficacy at the doses tested in the models studied. This comparative study offers a framework for understanding the renoprotective actions of these drugs and generates hypotheses for future investigation.