Molecular Characterization of the Effect of Glucagon-Like Peptide-1 Receptor Agonist Semaglutide in the Nephrotoxic Serum Nephritis Mouse Model.

BACKGROUND: CKD is a significant public health issue, affecting approximately half a billion people globally. Key risk factors for CKD include obesity, hypertension, cardiovascular diseases and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are effective treatments for obesity and diabetes. The FLOW trial recently showed that treatment with the GLP-1RA semaglutide significantly reduced the incidence of clinically important kidney outcomes in patients with type 2 diabetes and CKD, likely via beneficial effects on kidney blood flow, inflammation and fibrosis as well as effects mediated by improvement of glycemic control. This study aimed to characterize the effects of semaglutide in the mouse nephrotoxic serum nephritis model, a non-obese and non-diabetic mouse model of CKD. METHODS: Mice were treated with semaglutide or the angiotensin-converting enzyme inhibitor enalapril for 14 days. Various kidney function parameters were measured, and gene expression in key kidney compartments was explored using spatial transcriptomics and single-nucleus RNA sequencing in kidney samples collected at the end of the study. RESULTS: Semaglutide treatment significantly improved kidney function parameters and changed the expression of multiple genes involved in inflammatory processes and fibrosis, such as Spp1, and also affected gene-expression in the renin-angiotensin-aldosterone system. These findings from spatial transcriptomics were validated by histology, which also revealed semaglutide decreased mesangial expansion and had a beneficial effect on filtration slit density in the glomeruli. CONCLUSIONS: These findings demonstrate that the beneficial effects of semaglutide treatment in this rodent model of CKD can occur separately from its anti-obesity and anti-diabetes effects.