Semaglutide targets multi cell NLRP3 inflammasome and the senescence induced SASP in diabetic kidney disease

Semaglutide is a glucose-lowering drug used in the treatment of type 2 diabetes (T2DM). Outcomes from the FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial report that it improves kidney function and associated cardiovascular events, with benefits beyond glycaemic control. How Semaglutide protects our kidneys is unknown. Using human primary renal biopsy tissue and mice with advanced kidney disease, we previously identified a role for aberrant connexin-mediated hemichannels in activating the NOD-Like Receptor Protein-3 (NLRP3) inflammasome, stimulation of which is linked to cell senescence and its pro-inflammatory senescence-associated secretory phenotype (SASP). Additionally, we observed increased SASP biomarkers in plasma from people with T2-diabetic kidney disease, whilst macrophages from these individuals demonstrated increased markers cell of senescence. In conjunction with emerging evidence this preliminary data suggests that Semaglutide can significantly reduce pro-inflammatory events to protect the kidneys. Utilising a combination of in-vitro (primary proximal tubule epithelial cells, renal fibroblasts, and donor-derived macrophages; objective-1&2) and in-vivo (High-Fat Diet; objective-3) models, we will assess the efficacy of Semaglutide in regulating inflammation and decreasing the senescent cell burden. This study will provide mechanistic understanding of how Semaglutide protects the kidneys through suppression of NLRP3 inflammasome-induced inflammation, cell senescence, and the senescence-induced pro-inflammatory secretome.