Renal Effects of Semaglutide in Adolescent Mice

Background: Adolescent obesity is a threat to public health and is a major risk factor for the development of CKD, such as diabetic kidney disease. Therapeutic efforts have been made to address obesity and type 2 diabetes. One of the most prominent treatments is GLP-1 receptor agonist semaglutide, a drug originally developed for diabetes that has gained widespread use for its weight loss effects. However, the long-term effects of semaglutide in adolescents, particularly its impact on renal physiology and its underlying molecular mechanisms, remain poorly understood. Methods: 5 week old 6.BKS(D)-Leprdb/J male mice, a model of adolescent diabetes/obesity, were treated s.c. three times weekly with vehicle or 40 µg/kg/bw semaglutide for 8 weeks. Weekly measures of food intake and body weight were recorded. Glucose tolerance test, dual-energy X-ray absorptiometry analysis, glomerular filtration rate (GFR), microbiome analysis, renal proteomic and lipidomic analysis, and electron microscopy analysis were applied to assess kidney function and explore changes in molecular mechanisms. Results: Endpoint measures revealed a 17.81% reduction in body weight, reduced food intake, and improved glucose handling in semaglutide-treated mice over 8 weeks. We observed no declines in parameters of bone density and lean mass. Improved GFR was found in our semaglutide group. Preliminary kidney cortex proteomic data identified 71 proteins significantly changed in the semaglutide group compared to controls. An upregulated protein of interest, Ren1, at the local kidney level, can activate Mas1 signaling, thus mitigating Nf-kB-driven fibrosis/inflammation. Transmission electron microscopy analysis of the glomerular filtration barrier revealed decreased glomerular basement thickening and increased slit diagram length in the semaglutide group compared to controls. Conclusion: Our data reveals that semaglutide use throughout adolescence affects body weight and has at least partial reno-protective effect. Further work is needed to elucidate the systemic effects and safety profile of long-term Semaglutide use by adolescents and explore molecular mechanisms leading to these effects.