NLRP3 炎性小体抑制可通过抑制脂滴蓄积改善糖尿病肾病足细胞损伤。
Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy.
机构信息
Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Kidney Disease, Shijiazhuang 050017, China.
Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.
出版信息
Metabolism. 2021 May;118:154748. doi: 10.1016/j.metabol.2021.154748. Epub 2021 Mar 4.
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.
背景
核苷酸富含白细胞介素-1 受体相关蛋白 3（NLRP3）炎症小体已被证实是治疗代谢性疾病和炎症性疾病的有效靶点。我们最近的研究表明，抑制 NLRP3 炎症小体的激活可抑制糖尿病肾病中的肾脏炎症和纤维化。本研究旨在探讨 NLRP3 炎症小体在糖尿病肾病中对足细胞损伤的作用及其潜在机制。
方法
体内，db/db 小鼠用 NLRP3 炎症小体特异性抑制剂 MCC950 处理。NLRP3 敲除（NKO）小鼠经腹腔注射链脲佐菌素（STZ）诱导糖尿病。我们评估了糖尿病小鼠的肾功能、蛋白尿、足细胞损伤和肾小球脂质蓄积。体外，在高糖（HG）条件下，用 NLRP3 siRNA 或 MCC950 干扰足细胞，评估细胞凋亡、细胞骨架变化、脂质蓄积、NF-κB p65 激活和活性氧（ROS）生成。此外，在暴露于正常葡萄糖（NG）或 HG 的情况下，探讨了白细胞介素-1β（IL-1β）对脂质蓄积的作用和机制。
结果
MCC950 治疗改善了 db/db 小鼠的肾功能，减轻了蛋白尿、系膜扩张、足细胞丢失和肾小球脂质蓄积。NLRP3 敲除小鼠逆转了糖尿病诱导的足细胞丢失和肾小球脂质蓄积。MCC950 处理或糖尿病小鼠 NLRP3 敲除后，足细胞中固醇调节元件结合蛋白 1（SREBP1）和 SREBP2 的表达增加，三磷酸腺苷结合盒转运体 A1（ABCA1）的表达减少。体外，NLRP3 siRNA 或 MCC950 处理显著抑制了 HG 诱导的培养足细胞凋亡、细胞骨架变化、脂质蓄积、NF-κB p65 激活和线粒体 ROS 产生。此外，BAY11-7082 或 tempol 处理抑制了 HG 诱导的足细胞脂质蓄积。此外，IL-1β 暴露于足细胞可诱导脂质蓄积、NF-κB p65 激活和线粒体 ROS 生成。
结论
抑制 NLRP3 炎症小体通过抑制糖尿病肾病中的脂质蓄积来保护足细胞免受损伤。IL-1β/ROS/NF-κB p65 介导了糖尿病相关的足细胞脂质蓄积。抑制 NLRP3 炎症小体的激活可能是治疗糖尿病肾病的有效方法。
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