RGD Reference Report - Autoantibody-mediated angiotensin receptor activation contributes to preeclampsia through tumor necrosis factor-alpha signaling. - Rat Genome Database

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Autoantibody-mediated angiotensin receptor activation contributes to preeclampsia through tumor necrosis factor-alpha signaling.

Authors: Irani, RA  Zhang, Y  Zhou, CC  Blackwell, SC  Hicks, MJ  Ramin, SM  Kellems, RE  Xia, Y 
Citation: Irani RA, etal., Hypertension. 2010 May;55(5):1246-53. doi: 10.1161/HYPERTENSIONAHA.110.150540. Epub 2010 Mar 29.
RGD ID: 7248777
Pubmed: PMID:20351341   (View Abstract at PubMed)
PMCID: PMC3380607   (View Article at PubMed Central)
DOI: DOI:10.1161/HYPERTENSIONAHA.110.150540   (Journal Full-text)

Preeclampsia is a prevalent life-threatening hypertensive disorder of pregnancy for which the pathophysiology remains largely undefined. Recently, a circulating maternal autoantibody, the angiotensin II type I (AT(1)) receptor agonistic autoantibody (AA), has emerged as a contributor to disease features. Increased circulating maternal tumor necrosis factor alpha (TNF-alpha) is also associated with the disease; however, it is unknown whether this factor directly contributes to preeclamptic symptoms. Here we report that this autoantibody increases the proinflammatory cytokine TNF-alpha in the circulation of AT(1)-AA-injected pregnant mice but not in nonpregnant mice. Coinjection of AT(1)-AA with a TNF-alpha neutralizing antibody reduced cytokine availability in AT(1)-AA-injected pregnant mice. Moreover, TNF-alpha blockade in AT(1)-AA-injected pregnant mice significantly attenuated the key features of preeclampsia. Autoantibody-induced hypertension was reduced from 131+/-4 to 110+/-4 mm Hg, and proteinuria was reduced from 212+/-25 to 155+/-23 microg of albumin per milligram of creatinine (both P<0.05). Injection of AT(1)-AA increased the serum levels of circulating soluble fms-like tyrosine kinase 1 and soluble endoglin (34.1+/-5.1, 2.4+/-0.3 ng/mL, respectively) and coinjection with the TNF-alpha blocker significantly reduced their levels (21.7+/-3.4 and 1.2+/-0.4 ng/mL, respectively). Renal damage and placental abnormalities were also decreased by TNF-alpha blockade. Lastly, the elevated circulating TNF-alpha in preeclamptic patients is significantly correlated with the AT(1)-AA bioactivity in our patient cohort. Similarly, the autoantibody, through AT(1) receptor-mediated TNF-alpha induction, contributed to increased soluble fms-like tyrosine kinase 1, soluble endoglin secretion, and increased apoptosis in cultured human villous explants. Overall, AT(1)-AA is a novel candidate that induces TNF-alpha, a cytokine that may play an important pathogenic role in preeclampsia.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ENGHumanpre-eclampsia treatmentISOEng (Mus musculus) RGD 
EngRatpre-eclampsia treatmentISOEng (Mus musculus) RGD 
EngMousepre-eclampsia treatmentIDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Eng  (endoglin)

Genes (Mus musculus)
Eng  (endoglin)

Genes (Homo sapiens)
ENG  (endoglin)


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