Semaglutide reduces kidney disease severity and improves vascular endothelial function in mice with polycystic kidney disease in a diet-dependent manner

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by kidney cyst growth leading to kidney failure by mid-life. Cardiovascular complications are a major cause of mortality and preceded by impaired vascular endothelial function. In recent years, our group showed that disease severity in patients independently associates with increasing visceral adiposity. Glucagon-like peptide-1 receptor agonists (GLP1Ra[s]) are an appealing treatment option beyond the established weight loss effects, due to their anti-inflammatory and antioxidant effects, both driving kidney and endothelial pathologies in ADPKD. We hypothesized that semaglutide (SG), a FDA-approved GLP1Ra, would slow kidney disease and improve endothelial function in a preclinical model of ADPKD (Pkd1 p.R3277C [Pkd1RC/RC]; orthologous to human ADPKD). Adult (2.5 months [mo]) male and female C57Bl6/J Pkd1RC/RC mice were randomly assigned to feed on normal fat (12.6%; ConD) or high fat (42%; HFD) diet ad libitum for 3.5mo. Following, while continuing respective diets, mice received daily saline or SG (0.4 mg/kg, subcutaneous) injections for 5mo until euthanized at 11mo (n=11-15/sex/diet/treatment). Mice underwent magnetic resonance imaging (MRI) to evaluate height-adjusted total kidney volume (htTKV) and echoMRI to assess adiposity pre- and post-SG-treatment. Endothelium-dependent dilation (EDD) was measured via pressure myography in isolated carotid arteries. Comparing end-of-study to SG treatment initiation, SG-treated mice on HFD lost 5.6±1.1% body weight (BW) and 18.4±3.8% of their fat mass while saline-treated mice on HFD gained 3.6±1.2% BW (p< 0.001) and 11.7±4.7% of their fat mass (p< 0.001). Importantly, htTKV increased only 1.5±3.7% in SG-treated mice on HFD while saline-treated mice on HFD had a 14.9±4.3% increase in htTKV (p=0.02). Moreover, SG-treated mice on HFD had lower kidney weights (SG: 4.9±0.2, saline: 5.5±0.2g, p=0.01) versus saline-treated mice on HFD. Mice on ConD treated with SG did not exhibit changes in BW, fat mass, kidney weight, or htTKV by the end of treatment compared to saline-treated mice on ConD. Irrespective of diet, EDD to increasing doses of acetylcholine was similarly impaired in mice with ADPKD compared to historic, age-matched wildtype (WT) C57Bl6/J mice (peak EDD ConD: 83.1±2.1%, HFD: 85.4±2.4%, p=0.45; WT: 94.5±1.5%, p=0.02 vs. ADPKD vessels). Peak EDD was restored to WT levels by SG in mice on ConD (91.8±1.8%, p=0.006) but not on HFD (88.1±2.3%, p=0.37). Further, pre-incubating vessels with the antioxidant 4-hydroxy-TEMPO improved peak EDD in saline-treated mice on ConD (95.4±2.0%, p=0.002) with no further increase in SG-treated mice on ConD (94.5±1.7%, p=0.14), suggesting SG improves endothelial function by alleviating oxidative stress. Overall, our study confirms that semaglutide is an effective therapeutic to reduce adiposity and, in parallel, slow disease progression in HFD-fed mice with ADPKD, while potentially eliciting vascular protection in ConD-fed mice with ADPKD. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.