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Human placental renin–angiotensin system in normotensive and pre-eclamptic pregnancies at high altitude and after acute hypoxia–reoxygenation insult

Kurlak, L.O.; Mistry, Hiten D.; Cindrova-Davies, Tereza; Burton, Graham; Broughton Pipkin, Fiona

Authors

L.O. Kurlak lesia.kurlak@nottingham.ac.uk

Hiten D. Mistry hiten.mistry@nottingham.ac.uk

Tereza Cindrova-Davies

Graham Burton

Fiona Broughton Pipkin



Abstract

A 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 3100 m, 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 type 1 receptor (AT1R, P = 0.006) and type 2 receptor (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.

Journal Article Type Article
Publication Date Mar 1, 2016
Journal Journal of Physiology
Print ISSN 0022-3751
Electronic ISSN 1469-7793
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 594
Issue 5
APA6 Citation Kurlak, L., Mistry, H. D., Cindrova-Davies, T., Burton, G., & Broughton Pipkin, F. (2016). Human placental renin–angiotensin system in normotensive and pre-eclamptic pregnancies at high altitude and after acute hypoxia–reoxygenation insult. Journal of Physiology, 594(5), doi:10.1113/JP271045
DOI https://doi.org/10.1113/JP271045
Keywords renin-angiotensin system; hypoxia, placenta; hypoxia-re-oxygenation; hypoxia-inducible factors
Publisher URL http://onlinelibrary.wiley.com/doi/10.1113/JP271045/full
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information This is the peer reviewed version of the following article: Kurlak, L. O., Mistry, H. D., Cindrova-Davies, T., Burton, G. J. and Pipkin, F. B. (2016), Human placental renin–angiotensin system in normotensive and pre-eclamptic pregnancies at high altitude and after acute hypoxia–reoxygenation insult. J Physiol, 594: 1327–1340, which has been published in final form at http://dx.doi.org/. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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