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

Nestoridi, Eirini; Kushak, Rafail I.; Tsukurov, Olga; Grabowski, Eríc F.; Ingelfinger, Julie R.

doi:10.1007/s00467-007-0636-6

Cited by 28 publications

(21 citation statements)

References 32 publications

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“…64 In addition to its effect on platelets and monocytes, Stx induces tissue factor expression on endothelial cells. [91][92][93] Tissue factor is the receptor for coagulation factor VII, thus converting factor X to Xa in the extrinsic pathway. Tissue factor expression will trigger thrombin generation, resulting in clot formation and further platelet activation.…”

Section: Subtilase Cytotoxinmentioning

confidence: 99%

Pathophysiology of Typical Hemolytic Uremic Syndrome

Karpman

Sartz

Johnson

2010

Semin Thromb Hemost

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The typical form of hemolytic uremic syndrome (HUS) is associated with enterohemorrhagic ESCHERICHIA COLI (EHEC) infection. The disease process is initiated and perpetuated by interactions between the pathogen or its virulence factors and host cells, as well as the host response. During EHEC-associated HUS, alterations occurring at the intestinal mucosal barrier and in the circulation, as well as on endothelial cells and other target-organ cells, lead to cell activation and/or cytotoxicity, and trigger a prothrombotic state. This review summarizes current knowledge regarding the interactions of the pathogen and its virulence factors with cells in the intestine, bloodstream, kidney, and brain. Mechanisms of bacterial colonization, toxin circulation, and induction of target organ damage are discussed.

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Section: Subtilase Cytotoxinmentioning

confidence: 99%

Pathophysiology of Typical Hemolytic Uremic Syndrome

Karpman

Sartz

Johnson

2010

Semin Thromb Hemost

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“…11 Consistent with that concept, pharmacological angiotensin-converting enzyme (ACE) inhibition and AngII-type 1 receptor (AR) blockade downregulated TF stimulation in response to inflammatory agonists in experimental animals 12 and in vitro systems. 13,14 The RAS, however, is a multistep peptidergic system primarily controlled by renin activation, the rate-limiting step in the biological cascade to form AngII, 15 raising the issue of the effect of renin inhibition on TF expression, a so far unanswered research question.…”

Section: Introductionmentioning

confidence: 99%

Aliskiren, a renin inhibitor, downregulates TNF-α-induced tissue factor expression in HUVECS

Fiorentino

Cianchetti

Celi

et al. 2010

J Renin Angiotensin Aldosterone Syst

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Angiotensin (Ang)II, the effector arm of the locally active renin-angiotensin system (RAS), modulates Tissue Factor (TF), the principal initiator of blood coagulation and a key promoter of atherothrombotic events. Consistent with that knowledge, previous data showed inhibitory properties of angiotensin-converting enzyme inhibitor (ACEI)s and angiotensin II type-1 receptor blocker (ARB)s, but no data are available about the effect of renin inhibition. We aimed to evaluate whether aliskiren, a direct renin inhibitor (DRI), modulates TNF-α-stimulated TF expression in cultured human umbilical vein endothelial cells (HUVECs). Zofenopril, an ACEI, and olmesartan, an ARB, were the controls. HUVECs were incubated with experimental drugs (1 nM) 30 min prior to TNF-α stimulation (0.1 ng/ml × 4 h). Main evaluation variables were procoagulant activity (single-stage clotting assay), TF antigen (ELISA) and mRNA expression (realtime polymerase chain reaction) in cell lysates. TNF-α stimulated procoagulant activity and increased TF antigen and mRNA expression. Aliskiren inhibited TNF-α-mediated TF stimulation; zofenopril and olmesartan exerted a comparable effect. We conclude that aliskiren, a DRI, downregulates TNF-α-stimulated TF expression in HUVECs, possibly as a reflection of endothelial renin activation by the cytokine.

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“…Indeed, early workers employed an ACE activity assay to characterize human GEnCs (hGEnCs) in vitro (53). Nevertheless, studies focused on intrinsic RAS enzyme profiling in hGEnCs solely explored the expression of ACE, but did not determine whether other functional RAS-related enzymatic pathways are contained in them (18,33). The purpose of our investigation was to characterize the enzymatic cleavage of ANG peptides by hGEnCs using a mass spectrometry (MS)-based technique as analytical tool.…”

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confidence: 99%

Enzymatic processing of angiotensin peptides by human glomerular endothelial cells

Velez

Ierardi

Bland

et al. 2012

American Journal of Physiology-Renal Physiology

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The intraglomerular renin-angiotensin system (RAS) is linked to the pathogenesis of progressive glomerular diseases. Glomerular podocytes and mesangial cells play distinct roles in the metabolism of angiotensin (ANG) peptides. However, our understanding of the RAS enzymatic capacity of glomerular endothelial cells (GEnCs) remains incomplete. We explored the mechanisms of endogenous cleavage of ANG substrates in cultured human GEnCs (hGEnCs) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and isotope-labeled peptide quantification. Overall, hGEnCs metabolized ANG II at a significantly slower rate compared with podocytes, whereas the ANG I processing rate was comparable between glomerular cell types. ANG II was the most abundant fragment of ANG I, with lesser amount of ANG-(1-7) detected. Formation of ANG II from ANG I was largely abolished by an ANG-converting enzyme (ACE) inhibitor, whereas ANG-(1-7) formation was decreased by a prolylendopeptidase (PEP) inhibitor, but not by a neprilysin inhibitor. Cleavage of ANG II resulted in partial conversion to ANG-(1-7), a process that was attenuated by an ACE2 inhibitor, as well as by an inhibitor of PEP and prolylcarboxypeptidase. Further fragmentation of ANG-(1-7) to ANG-(1-5) was mediated by ACE. In addition, evidence of aminopeptidase N activity (APN) was demonstrated by detecting amelioration of conversion of ANG III to ANG IV by an APN inhibitor. While we failed to find expression or activity of aminopeptidase A, a modest activity attributable to aspartyl aminopeptidase was detected. Messenger RNA and gene expression of the implicated enzymes were confirmed. These results indicate that hGEnCs possess prominent ACE activity, but modest ANG II-metabolizing activity compared with that of podocytes. PEP, ACE2, prolylcarboxypeptidase, APN, and aspartyl aminopeptidase are also enzymes contained in hGEnCs that participate in membrane-bound ANG peptide cleavage. Injury to specific cell types within the glomeruli may alter the intrarenal RAS balance.

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

Cited by 28 publications

References 32 publications

Pathophysiology of Typical Hemolytic Uremic Syndrome

Pathophysiology of Typical Hemolytic Uremic Syndrome

Aliskiren, a renin inhibitor, downregulates TNF-α-induced tissue factor expression in HUVECS

Enzymatic processing of angiotensin peptides by human glomerular endothelial cells

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