Neutrophil Extracellular Traps Induce Glomerular Endothelial Cell Dysfunction and Pyroptosis in Diabetic Kidney Disease
Fengfan Zheng, Linqiang Ma, Xuan Li, Zhihong Wang, Rufei Gao, Chuan Peng, Bing Kang, Yue Wang, Ting Luo, Jinshan Wu, Yi Yang, Lilin Gong, Qifu Li, Shumin Yang, Jinbo Hu
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Neutrophil extracellular traps (NETs) are 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 NETs were degraded 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-knockout mice with streptozotocin-induced diabetes. In vitro, NETs-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 is promoted by NETs.