SGLT2 inhibitor canagliflozin alleviates vascular calcification through suppression of NLRP3 inflammasome

Aims: Vascular calcification is prevalent in pathological processes such as diabetes, chronic kidney disease (CKD) and atherosclerosis, but effective therapies are still lacking by far. Canagliflozin (CANA), an SGLT2 Inhibitor, has been approved for the treatment of type 2 diabetes mellitus and exhibits beneficial effects against Cardiovascular Disease. However, the effect of CANA on vascular calcification remains unknown. In this study, we hypothesize that CANA protects against vascular calcification.

Methods and results: Micro-computed tomography analysis and alizarin red staining revealed that CANA treatment prevented aortic calcification in CKD rats and in VitD3-overloaded mice. Moreover, CANA alleviated calcification of rat and human arterial rings. Alizarin red staining revealed that calcification of rat and human vascular smooth muscle cells (VSMCs) was attenuated by CANA treatment and this phenomenon was confirmed by calcium content assay. In addition, CANA downregulated the expression of osteogenic differentiation markers Runx2 and BMP2. Of interest, qPCR and western blot analysis revealed that CANA downregulated the expression of NLRP3, and the downstream signaling molecules Caspase-1 and IL-1β in VSMCs as well. Both NLRP3 Inhibitor MCC950 and knockdown of NLRP3 by siRNA independently resulted in decreased calcification of VSMCs. By contrast, activation of NLRP3 exacerbated VSMC calcification, and this effect was prevented by addition of CANA.

Conclusions: Our study for the first time demonstrates that CANA exerts a protective effect on vascular calcification at least partially via suppressing NLRP3 signaling pathway. Therefore, supplementation of CANA as well as inhibition of NLRP3 inflammasome presents a potential therapy for vascular calcification.

NLRP3; canagliflozin; chronic kidney disease; vascular calcification; vascular smooth muscle cell.