Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy
Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy
复制标题
NF-κB受体激活剂介导糖尿病肾病足细胞损伤
DOI：
10.1016/j.kint.2021.04.036
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发表时间：
2021-07-19
影响因子：
19.6
通讯作者：
Liu, Shuangxin
中科院分区：
文献类型：
--
作者：
Ke, Guibao;Chen, Xueqin;Liu, Shuangxin
糖尿病肾病患者足细胞中NF-κ B受体激活因子（RANK）表达增加然而，RANK与糖尿病肾病病理学的相关性仍不清楚。为了评价足细胞RANK在糖尿病肾病发生中的作用，我们建立了足细胞特异性RANK耗竭（RANK（-/-）Cre T）小鼠模型和足细胞特异性RANK过表达（RANK TG）模型，并在这些小鼠中用链脲佐菌素诱导糖尿病。我们发现，足细胞RANK耗竭可减轻蛋白尿、系膜基质扩张和基底膜增厚，而RANK过表达加重链脲佐菌素治疗小鼠的这些指标。此外，链脲霉素引发的氧化应激在RANK过表达中增加，但在RANK缺失小鼠中减少。特别是，NADPH氧化酶4及其专性伴侣P22 phox的表达在RANK过表达中增强，但在RANK缺失小鼠中减少。同时，RANK过表达小鼠足细胞核中的转录因子p65增加，但RANK缺失小鼠中的转录因子p65减少。在体外，高糖处理的足细胞在很大程度上复制了相关的发现。机制上，p65可以结合到NADPH氧化酶4和P22 phox的启动子区域，并增加足细胞中各自的基因启动子活性，这取决于RANK的水平。综上所述，这些结果表明，高糖诱导足细胞中的RANK，并通过p65引起NADPH氧化酶4和P22 phox的增加，可能与细胞因子TNF-α、MAC-2和IL-1 β一起导致足细胞损伤。因此，我们发现足细胞RANK在糖尿病环境中被诱导，RANK可能通过促进肾小球氧化应激和促炎细胞因子的产生介导糖尿病肾病的发生。
Receptor activator of NF-kappa B (RANK) expression is increased in podocytes of patients with diabetic nephropathy. However, the relevance of RANK to diabetic nephropathy pathobiology remains unclear. Here, to evaluate the role of podocyte RANK in the development of diabetic nephropathy, we generated a mouse model of podocyte-specific RANK depletion (RANK(-/-)Cre T), and a model of podocyte-specific RANK overexpression (RANK TG), and induced diabetes in these mice with streptozotocin. We found that podocyte RANK depletion alleviated albuminuria, mesangial matrix expansion, and basement membrane thickening, while RANK overexpression aggravated these indices in streptozotocin-treated mice. Moreover, streptozotocin-triggered oxidative stress was increased in RANK overexpression but decreased in the RANK depleted mice. Particularly, the expression of NADPH oxidase 4, and its obligate partner, P22phox, were enhanced in RANK overexpression, but reduced in RANK depleted mice. In parallel, the transcription factor p65 was increased in the podocyte nuclei of RANK overexpressing mice but decreased in the RANK depleted mice. The relevant findings were largely replicated with high glucose-treated podocytes in vitro. Mechanistically, p65 could bind to the promoter regions of NADPH oxidase 4 and P22phox, and increased their respective gene promoter activity in podocytes, dependent on the levels of RANK. Taken together, these findings suggested that high glucose induced RANK in podocytes and caused the increase of NADPH oxidase 4 and P22phox via p65, possibly together with the cytokines TNF-alpha, MAC-2 and IL-1 beta, resulting in podocyte injury. Thus, we found that podocyte RANK was induced in the diabetic milieu and RANK mediated the development of diabetic nephropathy, likely by promoting glomerular oxidative stress and proinflammatory cytokine production.