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

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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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Acknowledgements

This work was supported by National Institutes of Health grants HL 33095, DK 71253 (EFG) and DK 58950 (JRI). The authors would like to thank Dr. Cheleste Thorpe for providing Stx-1, Dr. Yale Nemerson for providing anti-TF antibody, and Dr. James Hathcock for providing purified FXa.

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Authors and Affiliations

  1. Pediatric Nephrology Laboratory, MassGeneral Hospital for Children at Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Eirini Nestoridi, Olga Tsukurov & Julie R. Ingelfinger

  2. Cardiovascular Thrombosis Laboratory, MassGeneral Hospital for Children at Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Eirini Nestoridi, Rafail I. Kushak & Eric F. Grabowski

  3. Pediatric Nephrology, MassGeneral Hospital for Children at Massachusetts General Hospital, Harvard Medical School, Yawkey 6C, 55 Fruit Street, Boston, MA, 02114, USA

    Julie R. Ingelfinger

Authors
  1. Eirini Nestoridi
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  2. Rafail I. Kushak
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  3. Olga Tsukurov
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  4. Eric F. Grabowski
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  5. Julie R. Ingelfinger
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Corresponding author

Correspondence to Julie R. Ingelfinger.

Additional information

This work was supported by National Institutes of Health grants HL 33095, DK 71253 (EFG) and DK 58950 (JRI).

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Nestoridi, E., Kushak, R.I., Tsukurov, O. et al. Role of the renin angiotensin system in TNF-α and Shiga-toxin-induced tissue factor expression. Pediatr Nephrol 23, 221–231 (2008). https://doi.org/10.1007/s00467-007-0636-6

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  • DOI: https://doi.org/10.1007/s00467-007-0636-6

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