Tanshinone IIA Alleviates Pyroptosis through SIRT1/NLRP3 Pathway to Improve Diabetic Nephropathy

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and the efficacy of standard clinical therapies is presently limited. Evidence has shown that pyroptosis-mediated cell death promotes several diabetic complications including DN. Tanshinone IIA (Tan IIA), the main fat-soluble component of S. miltiorrhiza Bunge, possesses anti-inflammatory and anti-oxidant properties. However, its impact on pyroptosis in DN progression and the underlying molecular mechanisms remain unclear. The aim of this study was to investigate the effect of Tan IIA on pyroptosis in DN. To establish a DN mouse model, STZ was administered to the mice for five consecutive days via injection. The mice in the treatment group then received Tan IIA by gavage for 10 weeks. Our data revealed that Tan IIA inhibited caspase-1 and gasdermin D (GSDMD)-mediated pyroptosis and thereby alleviated renal injury. Compared with that of the DN mice or high glucose-evoked HK-2 cells, the silent information regulator 1 (SIRT1) expression was significantly elevated, and the NLR family pyrin domain containing 3 (NLRP3) expression was dramatically decreased following Tan IIA treatment. Most importantly, the suppression of SIRT1 remarkably abrogated both the protective effects of Tan IIA against DN and its inhibition on pyroptosis-related molecules. Collectively, our results suggest that Tan IIA protects against DN by inhibiting caspase-1 and GSDMD-mediated pyroptosis through the SIRT1/NLRP3 pathway.