Uremic serum damages endothelium by provoking excessive neutrophil extracellular trap formation

Abstract Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Endothelial cell (EC) dysfunction is a key CKD-specific risk factor; however, the mechanisms by which uremia harms the endothelium are still unclear. We report a role for excessive neut...

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Autores principales:	Hoi Woul Lee, Victor Nizet, Jung Nam An, Hyung Seok Lee, Young Rim Song, Sung Gyun Kim, Jwa-Kyung Kim
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d7d1b00b2323488588577bf7bafab8b6
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spelling	oai:doaj.org-article:d7d1b00b2323488588577bf7bafab8b62021-11-08T10:50:42ZUremic serum damages endothelium by provoking excessive neutrophil extracellular trap formation10.1038/s41598-021-00863-w2045-2322https://doaj.org/article/d7d1b00b2323488588577bf7bafab8b62021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00863-whttps://doaj.org/toc/2045-2322Abstract Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Endothelial cell (EC) dysfunction is a key CKD-specific risk factor; however, the mechanisms by which uremia harms the endothelium are still unclear. We report a role for excessive neutrophil extracellular trap (NET) formation induced by uremic serum on EC injury. Level of plasma nucleosome and myeloperoxidase-DNA, established in vivo markers of NETs, as well as intracellular adhesion molecule (ICAM)-1 were measured in hemodialysis (HD) patients and healthy volunteers (HV) and their prognostic role evaluated. For in vitro studies, HV-derived neutrophils and differentiated HL-60 cells by retinoic acid were used to determine the effect of uremic serum-induced NETs on human umbilical vein EC (HUVEC). The level of in vivo NETs was significantly higher in incident HD patients compared to HV, and these markers were strongly associated with ICAM-1. Specifically, nucleosome and ICAM-1 levels were independent predictors of a composite endpoint, all-cause mortality, or vascular access failure. In vitro, HD-derived uremic serum significantly increased NET formation both in dHL-60 and isolated neutrophils compared to control serum, and these NETs decreased EC viability and induced their apoptosis. In addition, the level of ICAM-1, E-selectin and von Willebrand factor in HUVEC supernatant was significantly increased by uremic serum-induced NETs compared to control serum-induced NETs. Dysregulated neutrophil activities in the uremic milieu may play a key role in vascular inflammatory responses. The high mortality and CVD rates in ESRD may be explained in part by excessive NET formation leading to EC damage and dysfunction.Hoi Woul LeeVictor NizetJung Nam AnHyung Seok LeeYoung Rim SongSung Gyun KimJwa-Kyung KimNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hoi Woul Lee Victor Nizet Jung Nam An Hyung Seok Lee Young Rim Song Sung Gyun Kim Jwa-Kyung Kim Uremic serum damages endothelium by provoking excessive neutrophil extracellular trap formation
description	Abstract Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Endothelial cell (EC) dysfunction is a key CKD-specific risk factor; however, the mechanisms by which uremia harms the endothelium are still unclear. We report a role for excessive neutrophil extracellular trap (NET) formation induced by uremic serum on EC injury. Level of plasma nucleosome and myeloperoxidase-DNA, established in vivo markers of NETs, as well as intracellular adhesion molecule (ICAM)-1 were measured in hemodialysis (HD) patients and healthy volunteers (HV) and their prognostic role evaluated. For in vitro studies, HV-derived neutrophils and differentiated HL-60 cells by retinoic acid were used to determine the effect of uremic serum-induced NETs on human umbilical vein EC (HUVEC). The level of in vivo NETs was significantly higher in incident HD patients compared to HV, and these markers were strongly associated with ICAM-1. Specifically, nucleosome and ICAM-1 levels were independent predictors of a composite endpoint, all-cause mortality, or vascular access failure. In vitro, HD-derived uremic serum significantly increased NET formation both in dHL-60 and isolated neutrophils compared to control serum, and these NETs decreased EC viability and induced their apoptosis. In addition, the level of ICAM-1, E-selectin and von Willebrand factor in HUVEC supernatant was significantly increased by uremic serum-induced NETs compared to control serum-induced NETs. Dysregulated neutrophil activities in the uremic milieu may play a key role in vascular inflammatory responses. The high mortality and CVD rates in ESRD may be explained in part by excessive NET formation leading to EC damage and dysfunction.
format	article
author	Hoi Woul Lee Victor Nizet Jung Nam An Hyung Seok Lee Young Rim Song Sung Gyun Kim Jwa-Kyung Kim
author_facet	Hoi Woul Lee Victor Nizet Jung Nam An Hyung Seok Lee Young Rim Song Sung Gyun Kim Jwa-Kyung Kim
author_sort	Hoi Woul Lee
title	Uremic serum damages endothelium by provoking excessive neutrophil extracellular trap formation
title_short	Uremic serum damages endothelium by provoking excessive neutrophil extracellular trap formation
title_full	Uremic serum damages endothelium by provoking excessive neutrophil extracellular trap formation
title_fullStr	Uremic serum damages endothelium by provoking excessive neutrophil extracellular trap formation
title_full_unstemmed	Uremic serum damages endothelium by provoking excessive neutrophil extracellular trap formation
title_sort	uremic serum damages endothelium by provoking excessive neutrophil extracellular trap formation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d7d1b00b2323488588577bf7bafab8b6
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Uremic serum damages endothelium by provoking excessive neutrophil extracellular trap formation

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