Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy
| Autor: | Chun-Yu Deng, Zhiming Ye, Xia Chen, Caoshuai Dou, Yingzhen Wen, Zhiwen Lian, Wenjian Wang, Juan Hu, Sijia Li, Wei Shi, Zhuo Li, Ruizhao Li, Guibao Ke, Qianmei Zhang, Jianchao Ma, Ruyi Liao, Xueqin Chen, Lixia Xu, Ting Lin, Wei Dong, Li Zhang, Yue Du, Houqin Xiao, Yuanhan Chen, Bohou Li, Fengxia Zhang, Chaosheng He, Zhonglin Feng, Shuangshuang Zhu, Shuangxin Liu, Jie Xiao, Xingchen Zhao, Minghao Zheng, Xinling Liang, Su-Juan Kuang, Hong Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty 030232 urology & nephrology Streptozocin Proinflammatory cytokine Podocyte Diabetic nephropathy Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Diabetes Mellitus medicine Albuminuria Animals Diabetic Nephropathies Receptor NADPH oxidase Receptor Activator of Nuclear Factor-kappa B biology Podocytes Activator (genetics) NF-κB medicine.disease 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry Nephrology biology.protein P22phox |
| Zdroj: | Kidney International. 100:377-390 |
| ISSN: | 0085-2538 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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