Astragaloside IV ameliorates diabetic nephropathy in db/db mice by inhibiting NLRP3 inflammasome‑mediated inflammation.

Abstract

Diabetic nephropathy (DN) is a primary cause of end-stage renal disease. Despite the beneficial effects of astragaloside IV (AS)-IV on renal disease, the underlying mechanism of its protective effects against DN has not been fully determined. The aims of the present study were to assess the effects of AS-IV against DN in db/db mice and to explore the mechanism of AS-IV involving the NLR family pyrin domain containing 3 (NLRP3), caspase-1 and interleukin (IL)-1β pathways. The 8-week-old db/db mice received 40 mg/kg AS-IV once a day for 12 weeks via intragastric administration. Cultured mouse podocytes were used to further confirm the underlying mechanism in vitro. AS-IV effectively reduced weight gain, hyperglycemia and the serum triacylglycerol concentration in db/db mice. AS-IV also reduced urinary albumin excretion, urinary albumin-to-creatinine ratio and creatinine clearance rate, as well as improved renal structural changes, accompanied by the upregulation of the podocyte markers podocin and synaptopodin. AS-IV significantly inhibited the expression levels of NLRP3, caspase-1 and IL-1β in the renal cortex, and reduced the serum levels of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1. In high glucose-induced podocytes, AS-IV significantly improved the expression levels of NLRP3, pro-caspase-1 and caspase-1, and inhibited the cell viability decrease in a dose-dependent manner, while NLRP3 overexpression eliminated the effect of AS-IV on podocyte injury and the inhibition of the NLRP3 and caspase-1 pathways. The data obtained from in vivo and in vitro experiments demonstrated that AS-IV ameliorated renal functions and podocyte injury and delayed the development of DN in db/db mice via anti-NLRP3 inflammasome-mediated inflammation.