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

This study compared three GLP-1 receptor agonists—semaglutide, tirzepatide, and retatrutide—for their anti-fibrotic and anti-inflammatory effects in non-diabetic renal fibrosis, using HK-2 cells and mouse models of kidney injury and aging. Retatrutide was the most effective at the doses tested, but each drug showed a distinct pattern of pathway activity. The findings provide a framework for understanding how these drugs might protect the kidney.

Journal article — comparative preclinical in vitro and murine study. Population: HK-2 cells and mice with UUO-induced renal fibrosis and aged mice. Interventions: semaglutide; tirzepatide; retatrutide.

In UUO mice, semaglutide's effects were linked to PI3K-AKT inhibition, tirzepatide's to PI3K-AKT inhibition plus PPAR pathway activation, and retatrutide's to concurrent PI3K-AKT and NF-κB inhibition. In aged mice, all three drugs were associated with reduced G2/M arrest. Retatrutide was the most effective agent at the doses tested. The study did not report effect sizes or statistical values.

For researchers studying semaglutide, this paper provides comparative data on how semaglutide's renoprotective effects may differ from those of tirzepatide and retatrutide, specifically implicating PI3K-AKT inhibition in semaglutide's action in a non-diabetic fibrosis model. It does not establish that semaglutide is clinically effective for renal fibrosis in humans, nor does it provide dosing guidance.

Key findings

• In the UUO model, semaglutide was associated with PI3K-AKT inhibition, tirzepatide with PI3K-AKT inhibition and PPAR pathway activation, and retatrutide with inhibition of both PI3K-AKT and NF-κB pathways.
• In the aging model, all three drugs were linked to mitigation of G2/M arrest.
• Retatrutide showed the greatest efficacy at the doses tested among the three agents.
• The agents showed model- and drug-specific patterns of action rather than identical effects.

Limitations

• Preclinical models only (cell line and mice), so results may not translate directly to humans.
• The aging model and UUO model are non-diabetic, which may not fully represent diabetic nephropathy where these drugs are typically used.
• Doses tested are not specified in the abstract and may not correspond to clinically relevant exposures.

The record

• Journal: iScience 29(9): 117174
• Published: 2026-08-13
• PMID: 42630988 — DOI: 10.1016/j.isci.2026.117174
• Author countries: China

Peptide profiles: Semaglutide.

All indexed evidence: Semaglutide trials & papers.

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