Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy

Abstract

Background: Nucleotide leukin-rich polypeptide 3 (NLRP3) inflammasome is documented as a potent target for treating metabolic diseases and inflammatory disorders. Our recent work demonstrated that inhibition of NLRP3 inflammasome activation inhibits renal inflammation and fibrosis in diabetic nephropathy. This study was to investigate the effect of NLRP3 inflammasome on podocyte injury and the underlying mechanism in diabetic nephropathy.

Methods: In vivo, db/db mice were treated with MCC950, a NLRP3 inflammasome specific inhibitor. NLRP3 knockout (NKO) mice were induced to diabetes by intraperitoneal injections of streptozotocin (STZ). We assessed renal function, albuminuria, podocyte injury and glomerular lipid accumulation in diabetic mice. In vitro, apoptosis, cytoskeleton change, lipid accumulation, NF-κB p65 activation and reactive oxygen species (ROS) generation were evaluated in podocytes interfered with NLRP3 siRNA or MCC950 under high glucose (HG) conditions. In addition, the effect and mechanism of IL-1β on lipid accumulation was explored in podocytes exposed to normal glucose (NG) or HG.

Results: MCC950 treatment improved renal function, attenuated albuminuria, mesangial expansion, podocyte loss, as well as glomerular lipid accumulation in db/db mice. The diabetes-induced podocyte loss and glomerular lipid accumulation were reversed in NLRP3 knockout mice. The increased expression of sterol regulatory element-binding protein1 (SREBP1) and SREBP2, and decreased expression of ATP-binding cassette A1 (ABCA1) in podocytes were reversed by MCC950 treatment or NLRP3 knockout in diabetic mice. In vitro, NLRP3 siRNA or MCC950 treatment markedly inhibited HG-induced apoptosis, cytoskeleton change, lipid accumulation, NF-κB p65 activation, and mitochondrial ROS production in cultured podocytes. In addition, BAY11-7082 or tempol treatment inhibited HG-induced lipid accumulation in podocytes. Moreover, exposure of IL-1β to podocytes induced lipid accumulation, NF-κB p65 activation and mitochondrial ROS generation.

Conclusion: Inhibition of NLRP3 inflammasome protects against podocyte damage through suppression of lipid accumulation in diabetic nephropathy. IL-1β/ROS/NF-κB p65 mediates diabetes-associated lipid accumulation in podocytes. The suppression of NLRP3 inflammasome activation may be an effective therapeutic approach to diabetic nephropathy.

Keywords: Diabetic nephropathy; Lipid accumulation; NLRP3 inflammasome; Podocyte injury.