A clinical and experimental investigation of liraglutide effects on the brain-kidney axis

Liraglutide lowered plasma levels of the water-balance hormone arginine vasopressin (AVP) in healthy people. In rats, liraglutide changed the phosphorylation of synaptic proteins in the pituitary gland and altered the water channel aquaporin 2 in the kidney. The findings point to AVP suppression as a possible mechanism behind the cardiovascular and renal effects of liraglutide.

Journal article — Uncontrolled before-and-after open-label study plus rat/in vitro experiments. Population: Healthy humans in a single-centre open-label study; rats; in vitro pituitary-cell assay. Interventions: liraglutide.

Liraglutide reduced plasma arginine vasopressin levels in healthy humans. In the rat pituitary, quantitative proteomic and phosphoproteomic profiling showed time- and sex-dependent modifications to synaptic proteins. An in vitro AVP luciferase assay identified specific phosphosites that influence AVP release and mediate liraglutide-associated sex differences. In the kidney, investigation of AVP downstream signaling revealed posttranslational changes to aquaporin 2. The authors conclude that GLP-1 receptor agonist modulation of AVP release may account for cardiovascular and renal changes in patients.

For researchers studying liraglutide, this paper offers a mechanistic link between GLP-1 receptor activation and fluid balance through AVP suppression, pituitary synaptic protein signaling, and kidney aquaporin 2 handling. It does not establish clinical endpoints, dosing, or whether AVP reduction directly causes the cardiovascular and renal changes seen in patients.

Key findings

• In healthy humans, liraglutide reduced plasma arginine vasopressin (AVP) levels.
• In the rat pituitary gland, liraglutide produced time- and sex-dependent modifications to synaptic proteins.
• An in vitro AVP luciferase assay identified synaptic protein phosphosites that influence AVP release, including phosphosites linked to liraglutide-mediated sex differences.
• In the rat kidney, liraglutide caused posttranslational changes to aquaporin 2, a key AVP-regulated water channel.
• The authors conclude that GLP-1 receptor agonist modulation of AVP release may explain cardiovascular and renal changes observed in patients.

Limitations

• Single-centre, open-label, before-and-after design without a control arm.
• Rat and in vitro experiments may not directly translate to human physiology.
• The abstract does not report sample size, follow-up duration, or absolute effect sizes.

The record

• Journal: Science advances 12(32): eaef4951
• Published: 2026-08-05
• PMID: 42555711 — DOI: 10.1126/sciadv.aef4951
• MeSH terms: Kidney, Pituitary Gland, Brain, Animals, Humans, Rats, Proteomics, Signal Transduction, Phosphorylation, Female, Male, Aquaporin 2, Arginine Vasopressin, Glucagon-Like Peptide-1 Receptor, Liraglutide
• Funding: Medical Research Council
• Author countries: Saudi Arabia, Spain, UK

Peptide profiles: Liraglutide.

All indexed evidence: Liraglutide trials & papers.

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