Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy

足细胞 糖尿病肾病 肾损伤 受体 医学 激活剂(遗传学) 内科学 肾病 内分泌学 癌症研究 糖尿病 蛋白尿
作者
Guibao Ke,Xueqin Chen,Ruyi Liao,Lixia Xu,Li Zhang,Hong Zhang,Su‐Juan Kuang,Yue Du,Juan Hu,Zhiwen Lian,Caoshuai Dou,Qianmei Zhang,Xingchen Zhao,Fengxia Zhang,Shuangshuang Zhu,Jianchao Ma,Li Zhuo,Sijia Li,Chaosheng He,Xia Chen,Yingzhen Wen,Zhonglin Feng,Minghao Zheng,Ting Lin,Ruizhao Li,Bohou Li,Wei Dong,Yuanhan Chen,Wenjian Wang,Zhiming Ye,Chunyu Deng,Houqin Xiao,Jie Xiao,Xinling Liang,Wei Shi,Shuangxin Liu
出处
期刊:Kidney International [Elsevier]
卷期号:100 (2): 377-390 被引量:36
标识
DOI:10.1016/j.kint.2021.04.036
摘要

Receptor activator of NF-κB (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- α, MAC-2 and IL-1 β, 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.
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