Molecular Characterization of the Effect of Glucagon-Like Peptide-1 Receptor Agonist Semaglutide in the Nephrotoxic
Jaime Moreno Martinez1, Maria Ougaard, Tanya Grancharova
1Research and Early Development, Novo Nordisk A/S, Denmark.
Key Points:
Treatment with semaglutide improves kidney function and pathology in the mouse nephrotoxic serum nephritis model. Transcriptomics data demonstrated that semaglutide had anti-inflammatory and antifibrotic effects and indicated beneficial effects on renal hemodynamics. These beneficial effects of semaglutide occur independent of metabolic effects.
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 are effective treatments for obesity and diabetes. The FLOW trial recently showed that treatment with the glucagon-like peptide-1 receptor agonists semaglutide significantly reduced the incidence of clinically important kidney outcomes in patients with type 2 diabetes and CKD, likely through 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 nonobese and nondiabetic 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 that 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 antiobesity and antidiabetes effects.
Insights
Semaglutide improved kidney function in a mouse model of chronic kidney disease (CKD) independent of its effects on obesity and diabetes. This suggests potential benefits for kidney health beyond metabolic control.
Area of Science:
- Nephrology
- Pharmacology
Background:
- Chronic kidney disease (CKD) affects 500 million people globally, with obesity, hypertension, and diabetes as key risk factors.
- Glucagon-like peptide-1 receptor agonists (GLP-1RA) treat obesity and diabetes.
- The FLOW trial demonstrated semaglutide's efficacy in patients with type 2 diabetes and CKD.
Purpose of the Study:
- To investigate the effects of semaglutide on kidney function and gene expression in a non-diabetic, non-obese mouse model of CKD.
- To determine if semaglutide's kidney benefits are independent of its anti-obesity and anti-diabetic properties.
Main Methods:
- Mice with nephrotoxic serum nephritis (a model of CKD) were treated with semaglutide or enalapril for 14 days.
- Kidney function parameters were assessed.
- Spatial transcriptomics and single-nucleus RNA sequencing analyzed gene expression in kidney tissues.
- Histology validated transcriptomic findings.
Main Results:
- Semaglutide treatment significantly improved kidney function parameters.
- Gene expression analysis revealed modulation of inflammatory and fibrotic processes, including Spp1.
- Semaglutide impacted the renin-angiotensin-aldosterone system gene expression.
- Histology confirmed reduced mesangial expansion and improved glomerular filtration slit density.
Conclusions:
- Semaglutide demonstrates beneficial effects on kidney health in a rodent model of CKD.
- These kidney protective effects can be achieved independently of anti-obesity and anti-diabetic actions.
- Semaglutide shows promise for managing CKD through mechanisms beyond glycemic control and weight reduction.
