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dc.contributor.authorKurlak, Lesia Oen
dc.contributor.authorMistry, Hiten Den
dc.contributor.authorCindrova-Davies, Terezaen
dc.contributor.authorBurton, Grahamen
dc.contributor.authorBroughton, Pipkin Fionaen
dc.date.accessioned2015-10-30T11:20:27Z
dc.date.available2015-10-30T11:20:27Z
dc.date.issued2015-11-17en
dc.identifier.citationJournal of Physiology 2015.en
dc.identifier.issn0022-3751
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/252463
dc.description.abstractA functioning placental renin angiotensin system (RAS) appears necessary for uncomplicated pregnancy and is present during placentation, which occurs under low oxygen tensions. Placental RAS is increased in pre-eclampsia (PE), characterised by placental dysfunction and elevated oxidative stress. We investigated the effect of high-altitude hypoxia on the RAS and hypoxia-inducible factors (HIFs) by measuring mRNA and protein expression in term placentae from normotensive (NT) and PE women who delivered at sea level or above 3100m; using an explant model of hypoxia-reoxygenation to assess the impact of acute oxidative stress on the RAS and HIFs. Protein levels of prorenin (P=0.049), prorenin receptor (PRR; P=0.0004), and angiotensin receptors (AT1R, P=0.006) and (AT2R, P=0.002) were all significantly higher in placentae from NT women at altitude, despite mRNA expression being unaffected. However, mRNA expression of all RAS components was significantly lower in PE at altitude than at sea level, yet PRR, angiotensinogen (AGT) and AT1R proteins were all increased. The increase in transcript and protein expression of all the HIFs and NADPH oxidase 4 seen in PE compared to NT at sea-level was blunted at high altitude. Experimentally-induced oxidative stress stimulated AGT mRNA (P=0.04) and protein (P=0.025). AT1R (r=0.77, P<0.001) and AT2R (r=0.81, P<0.001) mRNA both significantly correlated with HIF-1β, whilst AT2R also correlated with HIF-1α (r=0.512, P<0.013). Our observations suggest that the placental RAS is responsive to changes in tissue oxygenation: this could be important in the interplay between reactive oxygen species as cell-signalling molecules for angiogenesis and hence placental development and function.
dc.description.sponsorshipHDM is supported by an ERA-EDTA Fellowship (ERA LTF 137-2013).
dc.languageEnglishen
dc.language.isoenen
dc.publisherWiley
dc.subjectrenin angiotensin systemen
dc.subjecthypoxiaen
dc.subjectplacentaen
dc.subjecthypoxia-re-oxygenationen
dc.subjecthypoxia-inducible factorsen
dc.titleHuman placental renin-angiotensin system in normotensive and pre-eclamptic pregnancies at high altitude and after acute hypoxia-reoxygenation insult.en
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1113/JP271045en
prism.endingPage1340
prism.publicationDate2015en
prism.publicationNameJournal of Physiologyen
prism.startingPage1327
prism.volume594en
dcterms.dateAccepted2015-10-24en
rioxxterms.versionofrecord10.1113/JP271045en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-11-17en
dc.contributor.orcidCindrova-Davies, Tereza [0000-0002-9212-0514]
dc.contributor.orcidBurton, Graham [0000-0001-8677-4143]
dc.identifier.eissn1469-7793
rioxxterms.typeJournal Article/Reviewen
rioxxterms.freetoread.startdate2016-11-17


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