Zhang CongXiao, Zhu XinWang, Li LuLu, Ma TianKui, Shi Mai, Yang Ying, Fan QiuLing
Department of Nephrology, The First Hospital of China Medical University, Shenyang 110001, People's Republic of China.
Blood Purification Center, Shenyang the 4th Hospital of People, Shenyang 110031, People's Republic of China.
Diabetes Metab Syndr Obes. 2019 Aug 2;12:1297-1309. doi: 10.2147/DMSO.S199802. eCollection 2019.
Diabetic nephropathy (DN) is a lethal diabetic microvascular complication characterized by chronic low-grade inflammation. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the progression of DN. MCC950 is a selective and potent inhibitor of NLRP3; however, its efficacy in DN requires further investigation.
To investigate the efficacy of MCC950 in DN, eight-week-old type 2 diabetic mice received injections of MCC950 intraperitoneally (10 mg/kg) twice per week for 12 weeks. Urinary albumin-to-creatinine ratio (ACR) and neutrophil gelatinase-associated lipocalin (NGAL), renal function, pathological changes, markers of podocyte and fibrosis and NLPR3/caspase-1/IL-1β expression in the renal cortices of mice were evaluated. High-glucose (HG)-treated rat glomerular mesangial cells were treated with various concentrations of MCC950 for 48 hrs. Markers of fibrosis and NLPR3/caspase-1/IL-1β expression in the glomerular mesangial cells were measured.
The NLRP3 inflammasome was activated in mice and HG-induced mesangial cells by upregulating NLRP3/caspase-1/IL-1β pathway. Inhibition of the NLRP3 inflammasome with MCC950 reduced the production of active caspase-1 and active IL-1β in mice and HG-induced mesangial cells. MCC950 reduced serum creatinine, urinary ACR and NGAL, attenuated mesangial expansion with increased matrix and tubular dilatation, alleviated thickened glomerular basement membrane (GBM) and foot process fusion without affecting body weight and blood glucose levels in mice. MCC950 increased the expression of podocin in mice, and decreased the expression of TGF-β1, fibronectin, collagen I and α-smooth muscle actin (α-SMA) in renal cortices of mice and HG-induced mesangial cells.
MCC950 ameliorated renal function, thickened GBM, podocyte injury and renal fibrosis in mice, and decreased the production of fibrosis markers in HG-induced mesangial cells. MCC950 effectively ameliorated diabetic kidney injury by inhibiting NLRP3/caspase-1/IL-1β pathway, which may be a potential therapeutic strategy to prevent the progression of DN.
糖尿病肾病（DN）是一种以慢性低度炎症为特征的致命性糖尿病微血管并发症。含NOD样受体吡咯结构域蛋白3（NLRP3）炎性小体与DN的进展有关。MCC950是一种选择性且强效的NLRP3抑制剂；然而，其在DN中的疗效尚需进一步研究。
为研究MCC950在DN中的疗效，8周龄的2型糖尿病小鼠每周两次腹腔注射MCC950（10 mg/kg），共12周。评估小鼠肾皮质中的尿白蛋白与肌酐比值（ACR）和中性粒细胞明胶酶相关脂质运载蛋白（NGAL）、肾功能、病理变化、足细胞和纤维化标志物以及NLPR3/caspase-1/IL-1β表达。用不同浓度的MCC950处理高糖（HG）处理的大鼠肾小球系膜细胞48小时。检测肾小球系膜细胞中的纤维化标志物以及NLPR3/caspase-1/IL-1β表达。
NLRP3炎性小体在小鼠和HG诱导的系膜细胞中通过上调NLRP3/caspase-1/IL-1β途径被激活。用MCC950抑制NLRP3炎性小体可减少小鼠和HG诱导的系膜细胞中活性caspase-1和活性IL-1β的产生。MCC950降低了血清肌酐、尿ACR和NGAL，减轻了系膜扩张伴基质增加和肾小管扩张，缓解了肾小球基底膜（GBM）增厚和足突融合，且不影响小鼠体重和血糖水平。MCC950增加了小鼠中足细胞蛋白的表达，并降低了小鼠肾皮质和HG诱导的系膜细胞中TGF-β1、纤连蛋白、I型胶原和α平滑肌肌动蛋白（α-SMA）的表达。
MCC950改善了小鼠的肾功能、GBM增厚、足细胞损伤和肾纤维化，并降低了HG诱导的系膜细胞中纤维化标志物的产生。MCC950通过抑制NLRP3/caspase-1/IL-1β途径有效改善糖尿病肾损伤，这可能是预防DN进展的一种潜在治疗策略。
