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Published in: Pediatric Nephrology 2/2008

01-02-2008 | Original Article

Role of the renin angiotensin system in TNF-α and Shiga-toxin-induced tissue factor expression

Authors: Eirini Nestoridi, Rafail I. Kushak, Olga Tsukurov, Eric F. Grabowski, Julie R. Ingelfinger

Published in: Pediatric Nephrology | Issue 2/2008

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Abstract

Current evidence implicates a prothrombotic state in the development of Shiga-toxin (Stx)-mediated hemolytic uremic syndrome (HUS). We recently reported that Stx modulates procoagulant activity by enhancing functional tissue factor (TF) activity on cytokine-activated human glomerular endothelial cells (HGECs). Since angiotensin II (Ang II), the key effector of the renin angiotensin system (RAS), has been shown to increase TF expression in vascular tissue, we examined the possible involvement of Ang II in TF expression in HGECs. HGECs were exposed to tumor necrosis factor (TNF)-α ± Stx-1 ± Ang II. Exogenous Ang II significantly increased TF activity and TF mRNA in TNF-α- ± Stx-1-activated HGECs. This increase was mediated via Ang II type I receptor (AT1R), as losartan, an AT1R inhibitor, attenuated Ang-II-induced TF activity. To study the effect of endogenous Ang II in TF expression by TNF-α ± Stx-1, HGECs were incubated with losartan or an AT2R inhibitor (PD 123319) or an angiotensin-converting enzyme inhibitor (enalapril). Losartan but not PD 123319 decreased TF activity induced by TNF-α ± Stx-1 (P < 0.05). Enalapril, also, dose dependently, downregulated TF expression in HGECs exposed to TNF-α ± Stx-1 (P < 0.05). AT1R mRNA was upregulated in TNF-α- ± Stx-1-activated HGECs (P < 0.05). These data indicate that TF expression in TNF-α- and Stx-1-activated HGECs is enhanced by exogenous Ang II and that endogenous Ang II production may be upregulated by TNF-α ± Stx-1. Hence, local RAS activation may be important in the development of the thrombotic microangiopathy observed in HUS.
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Metadata
Title
Role of the renin angiotensin system in TNF-α and Shiga-toxin-induced tissue factor expression
Authors
Eirini Nestoridi
Rafail I. Kushak
Olga Tsukurov
Eric F. Grabowski
Julie R. Ingelfinger
Publication date
01-02-2008
Publisher
Springer-Verlag
Published in
Pediatric Nephrology / Issue 2/2008
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-007-0636-6

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