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Neutrophil extracellular traps induce glomerular endothelial cell dysfunction and pyroptosis in diabetic kidney disease

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posted on 2022-09-12, 19:32 authored by Fengfan Zheng, Linqiang Ma, Xuan Li, Rufei Gao, Chuan Peng, Bing Kang, Yue Wang, Ting Luo, Jinshan Wu, Yi Yang, Lilin Gong, Qifu Li, Shumin Yang, Jinbo Hu

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Neutrophil extracellular traps (NETs) is a network structure composed of loose chromatin and embedded with multiple proteins. Here, we observed increased NETs deposition in the glomeruli of DKD patients and diabetic mice (streptozotocin-induced or db/db mice). After degrading NETs with DNase I, diabetic mice exhibited attenuated glomerulopathy and glomerular endothelial cells (GECs) injury. We also observed alleviated glomerulopathy and GECs injury in peptidylarginine deiminase 4 (PAD4)-knockout mice with streptozotocin-induced diabetes. In vitro, NET-induced GECs pyroptosis was characterized by pore formation in the cell membrane, dysregulation of multiple genes involved in cell membrane function, and increased expression of pyroptosis-related proteins. Strengthening the GECs surface charge by oleylamine significantly inhibited NETs-induced GECs pyroptosis. These findings suggest that the GECs charge related pyroptosis is involved in DKD progression which promoted by NETs.

Funding

This work was supported by the National Natural Science Foundation of China , Major Joint Project (U21A20355), National Natural Science Foundation of China (81800731, 81870567, 81970720, 82000810 and 82170825), the China Postdoctoral Science Foundation (2019M663499), the Chongqing Postdoctoral Innovative Talents Support Project [2020(379)], Joint Medical Research Project of Chongqing Science and Technology Commission & Chongqing Health and Family Planning Commission (Major Project, 2021ZDXM002), the Natural Science foundation of Chongqing (cstc2020jcyj-bshX0081), Outstanding Talents of the First Affiliated Hospital of Chongqing Medical University 2019 (2019-4-22 for Dr Jinbo Hu), Chongqing Outstanding Youth Funds (cstc2019jcyjjq0006), Bethune Merck Diabetes Research Foundation (G2018030).

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