Angiotensin II triggers release of neutrophil extracellular traps, linking thromboinflammation with essential hypertension.

Akrivi Chrysanthopoulou,Maria Ntinopoulou,George S Georgiadis,Panagiotis Skendros,Alexandros Mitsios,Eugenia Gkaliagkousi,Stella Arelaki,Christos Argyriou,Panagiotis Pateinakis,Konstantinos Ritis,Alexandra Giatromanolaki,Christina Antoniadou,Vasileios Papadopoulos,Antonios Lazaridis

doi:10.1172/jci.insight.148668

Abstract

Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis, leading to target organ damage in essential hypertension (EH). However, the role of neutrophils in EH is still elusive. We investigated the association between angiotensin II (Ang II) and neutrophil extracellular traps (NETs) in pathogenesis of EH. Plasma samples, kidney biopsies, and surgical specimens of abdominal aortic aneurysms (AAAs) from patients with EH were used. Cell-based assays, NETs/human aortic endothelial cell cocultures, and in situ studies were performed. Increased plasma levels of NETs and tissue factor (TF) activity were detected in untreated, newly diagnosed patients with EH. Stimulation of control neutrophils with plasma from patients with untreated EH generated TF-enriched NETs promoting endothelial collagen production. Ang II induced NETosis in vitro via an ROS/peptidylarginine deiminase type 4 and autophagy-dependent pathway. Circulating NETs and thrombin generation levels were reduced substantially in patients with EH starting treatment with Ang II receptor blockers, whereas their plasma was unable to trigger procoagulant NETs. Moreover, TF-bearing NETotic neutrophils/remnants accumulated in sites of interstitial renal fibrosis and in the subendothelial layer of AAAs. These data reveal the important pathogenic role of an Ang II/ROS/NET/TF axis in EH, linking thromboinflammation with endothelial dysfunction and fibrosis.

Highlights

Essential hypertension (EH) is a major risk factor for cardiovascular disease (CVD) and chronic kidney disease (CKD), constituting a leading cause of morbidity and mortality [1, 2]
We detected significantly increased levels of these neutrophil extracellular traps (NETs) remnants in patients compared with healthy individuals of a similar profile (Figure 1, A and B)
We found that EH plasma–treated control neutrophils generated NETs, as assessed by immunofluorescence microscopy (Figure 1, D and E) and MPO/DNA complex ELISA (Figure 1F)

Summary

Introduction

Essential hypertension (EH) is a major risk factor for cardiovascular disease (CVD) and chronic kidney disease (CKD), constituting a leading cause of morbidity and mortality [1, 2]. Endothelial dysfunction, oxidative stress, and chronic low-grade inflammation have been documented to contribute to the initiation and maintenance of EH [3], leading to the prevalence of a proinflammatory and prothrombotic phenotype [4, 5]. In these procedures activation of the renin-angiotensin-aldosterone system holds a central pathogenetic role [6]. Recent emerging evidence has shown that in EH, an excessive or prolonged stimulation of innate immune cells mediates a chronic inflammatory state that promotes vascular injury and target organ damage [3]. Even though epidemiological studies have correlated neutrophil count with increased risk of developing EH and kidney dysfunction [8, 9], the experimental and clinical evidence regarding their exact role in the pathogenesis and complications of EH is limited [10]

Methods

Results

Conclusion