ESPE Abstracts

Background: Semaglutide is a glucagon-like peptide-1 receptor agonist which has been confirmed that it offered kidney-protective effects in patients with type 2 diabetes and chronic kidney disease. However, the exact mechanism by which Semaglutide exerts its reno-protection remains largely unknown.

Purpose: This study aim ed to investigate whether Semaglutide has beneficial effects in diabetic nephropathy mice via the gut-micriobiota-bile acid axis.

Study design and Methods: The DN model in mice was established by streptozotocin combined with a high-fat diet (STZ/HFD). Semaglutide was administered at dose of 30nmol/kg daily. Renal histological changes were measured by PAS and Masson staining. Western blotting, real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were performed to analyze the effects of Semaglutide on renal inflammation and fibrosis. 16S rRNA sequencing was utilized to analyze the composition of intestinal bacteria, and LC-MS/MS-based targeted metabolomics was used to identify the metabolite profile.

Results: After a 12- week of treatment, we found that Semaglutide significantly reduced urinary albumin excretion (UAE), and attenuated the pathological injuries of kidney in mice. In addition, we found that Semaglutide significantly altered the gut microbiota composition, and decreased total fecal bile acid. It also changed the serum levels of total bile acid (TBA) and BA profiles, such as β-muricholic acid (β-MCA), taurocholic acid (TCA), tauro β-muricholic acid (Tβ-MCA) and deoxycholic acid (DCA), which have been reported to be higher in patients with CKD. These BAs are associated with the activation of farnesoid X receptor (FXR), which is highly expressed in kidney. Through RT-qPCR and western blot analysis, upregulation of FXR was observed in DN mice with semaglutide treatment.

Conclusion: Our study revealed that Semaglutide significantly alleviated renal injuries in mice with DN. The gut microbiota-bile acid axis may be an important target for the reno-protection of Semaglutide in DN, and the activation of FXR may be the specific mechanism which needs further study.