Neutrophil Extracellular Traps Aggravate Contrast-Induced Acute Kidney Injury by Damaging Glomeruli and Peritubular Capillaries

Abstract

Heng Wang,1,* Tingting Gao,1,* Ruijing Zhang,2,* Jie Hu,1 Siqi Gao,1 Yuwen Wang,1 Xiaotong Qi,1 Yun Zhou,3 Guoping Zheng,1,4 Honglin Dong1 1Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 3Shanxi Provincial Integrated TCM and WM Hospital, Taiyuan, People’s Republic of China; 4Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia*These authors contributed equally to this workCorrespondence: Honglin Dong, Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan City, Shanxi Province, 030001, People’s Republic of China, Email [email protected] Guoping Zheng, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia, Email [email protected]: Contrast-induced acute kidney injury (CI-AKI) is considered to be the third leading cause of hospital-acquired kidney injury. Current studies mostly suggest that contrast agents mainly harm renal tubular epithelial cells, but we hypothesized that the development of CI-AKI should be the result of the interaction of renal vascular and tubular injury.Methods: First we constructed a CI-AKI mouse model and verified the success of the model by pathological injury and serum creatinine level. Immunohistochemistry, protein quantification and qRT-PCR were used to detect the location and level of expression of neutrophil extracellular traps (NETs) in the kidney. Then, we blocked the in vivo accumulation of NETs using GSK484 and DNase I and detected the expression of NETs and the damage of glomerular and peritubular capillaries.Results: We first identified the presence of NETs in CI-AKI mice, and NETs were mainly accumulated in glomeruli and peritubular capillaries. The expression of NETs was positively correlated with the severity of CI-AKI kidney. After inhibition of NETs release or promotion of NETs degradation by drugs, renal vascular endothelial cell injury was reduced and renal pathological changes and creatinine levels were reversed in CI-AKI mice. In addition, inhibition of NETs reduced apoptosis and pyroptosis of renal cells and attenuated inflammation in vivo.Conclusion: These findings suggest that NETs are involved in the development of CI-AKI by damaging glomerular and peritubular capillary endothelial cells. This study will provide a new strategy for clinical prevention and treatment of CI-AKI.Keywords: contrast-induced acute kidney injury, neutrophils, neutrophil extracellular traps, glomeruli, peritubular capillaries

Keywords

• contrast-induced acute kidney injury
• neutrophils
• neutrophil extracellular traps
• glomeruli
• peritubular capillaries