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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.
摘要：
糖尿病肾病（DN）是终末期肾病的主要原因。尽管黄芪甲苷（AS）IV对肾脏疾病有有益作用，其对DN的保护作用的潜在机制尚未完全确定。本研究的目的是评估AS-IV对db/db小鼠DN的影响，并探索AS-IV涉及NLR家族pyrin结构域包含3（NLRP3）的机制，caspase‑1和白介素(IL)‑1β途径。8周龄的db/db小鼠通过胃内给药每天一次接受40mg/kgAS‑IV，持续12周。使用培养的小鼠足细胞来进一步确认体外的潜在机制。AS-IV有效减少体重增加，db/db小鼠的高血糖和血清三酰甘油浓度。AS-IV也减少尿白蛋白排泄，尿白蛋白-肌酐比值和肌酐清除率，以及改善肾脏结构变化，伴随着足细胞标记podocin和突触素的上调。AS-IV显着抑制肾皮质中NLRP3，caspase‑1和IL‑1β的表达水平，并降低肿瘤坏死因子（TNF）-α和单核细胞趋化蛋白-1的血清水平。在高糖诱导的足细胞中，AS-IV显着提高了NLRP3，pro-caspase-1和caspase-1的表达水平，并以剂量依赖性方式抑制了细胞活力的降低。而NLRP3过表达消除了AS-IV对足细胞损伤的影响以及对NLRP3和caspase-1途径的抑制。从体内和体外实验获得的数据表明，AS-IV通过抗NLRP3炎性体介导的炎症改善了db/db小鼠的肾功能和足细胞损伤，并延迟了DN的发展。
