AdipoRon ameliorates vascular endothelial injury in type 2 diabetes mellitus and is associated with suppression of the NLRP3-Caspase-1-GSDMD pyroptosis axis

BACKGROUND: AdipoRon is a bioactive synthetic agonist of the adiponectin receptor. It has been demonstrated to improve glucose tolerance and mitigate insulin resistance. However, the long-term effects on vascular endothelial pyroptosis in type 2 diabetes mellitus (T2DM) remain poorly understood. This study aims to investigate whether AdipoRon exerts a protective effect against vascular endothelial pyroptosis in T2DM. METHODS: The expression levels of NLRP3 inflammasome-related proteins were measured by western blotting. Vascular endothelial pyroptosis was assessed using multiple approaches, including biochemical analysis, western blotting, flow cytometry analysis, tube formation assay, and immunofluorescent test, with each method detecting distinct relevant indexes. RESULTS: In high glucose (HG)-challenged human umbilical vein endothelial cells (HUVECs) and aortae of T2DM mice, the expression levels of NLRP3, ASC, pro-caspase-1, cleaved-caspase-1, GSDMD, and p-NF-κB p65 were significantly upregulated, with a concurrent reduction in Nrf2 protein level. Moreover, Oxidative stress-related indices, such as ROS, MDA, and GSH-Px, were increased, while SOD levels were decreased in both models. In HG-treated HUVECs, the levels of LDH and ET-1 were markedly elevated, the release of NO was suppressed, and tube formation ability was severely disrupted compared with the control group. Interestingly, AdipoRon treatment successfully reversed all these HG-induced aberrant alterations in vitro and in vivo. CONCLUSIONS: AdipoRon is a promising candidate compound for protecting against T2DM. Its endothelial protective effects are closely associated with the suppression of the NLRP3-Caspase-1-GSDMD axis-mediated pyroptosis. These findings provide novel insights into the development of a new therapeutic strategy for the clinical management of T2DM.