iScienceAug 22, 2026

Comparing semaglutide, tirzepatide, and retatrutide on kidney scarring in blocked and old mice

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 23, 2026

Abstract

Semaglutide, tirzepatide, and retatrutide exhibit distinct effects on renal fibrosis in various models.

Semaglutide's effects are linked to inhibition of the PI3K-AKT pathway.
Tirzepatide influences both the PI3K-AKT pathway and activates the PPAR pathway.
Retatrutide affects both the PI3K-AKT and NF-kB pathways simultaneously.
All three drugs are associated with reducing G2/M cell cycle arrest in an aging model.
Retatrutide demonstrated the highest efficacy among the drugs tested in the studied models.

Simplified

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.

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Comparing semaglutide, tirzepatide, and retatrutide on kidney scarring in blocked and old mice

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