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Preeclampsia, the Renin-Angiotensin-Aldosterone System and Beyond

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Preeclampsia, the Renin-Angiotensin-Aldosterone System and Beyond Preeclampsia, the Renin-Angiotensin-Aldosterone System and beyond Koen Verdonk Preeclampsia, the Renin-Angiotensin-Aldosterone System and beyond Thesis, Erasmus University, Rotterdam. With summary in Dutch and English. ISBN: 978-94-6203-831-8 Cover and chapter design: Simon Hattinga Verschure Printing: CPI Koninklijke Wöhrmann (www.cpibooks.com/nl/) Copyright ©Koen Verdonk All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system of any nature, or transmitted in any form or means, wihout written permission of the author, or when approriate, of the publishers of the publications. Preeclampsia, the Renin-Angiotensin-Aldosterone System and beyond Preeclampsie, het renine-angiotensine-aldosteron systeem en meer. Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.A.P. Pols en volgens besluit van het College voor Promoties De openbare verdediging zal plaatsvinden op woensdag 3 juni 2015 om 13.30 uur door Koen Verdonk geboren te Groningen Promotiecommissie Promotoren: Prof.dr. A.H.J. Danser Prof.dr. E.A.P. Steegers Overige leden: Prof.dr. J.A.M. van der Post Prof.dr. S. Sleijfer Prof.dr. R. Zietse Copromotoren: Dr. A.H. van den Meiracker Dr. W. Visser Contents Chapter 1 General introduction and aims 7 Part 1 Chapter 2 Angiotensin II type 2 receptor agonists: where should they be 13 applied? Expert Opin Investig Drugs. 2012, 21:4 , 501-513 Chapter 3 Compound 21 induces vasorelaxation via an endothelium- and 37 angiotensin II type 2 receptor-independent mechanism. Hypertension. 2012, 60:3,722-9 Part 2 Chapter 4 Urinary Markers of Intrarenal Renin-Angiotensin System 53 Activity In Vivo Curr Hypertens Rep. 2013, 15:2, 81-88 Chapter 5 Methodologic Issues in the Measurement of Urinary Renin 69 Clin J Am Soc Nephrol. 2014, 9:7, 1163-1167 Part 3 Chapter 6 Nieuwe inzichten in pathogenese van pre-eclampsie rol van 79 angiogeneseremmende factoren Ned Tijdschr Geneeskd. 2011;155:A2946 Chapter 7 The renin-angiotensin-aldosterone system in pre-eclampsia: 89 the delicate balance between good and bad Clin Sci (Lond). 2014, 126:8, 537-44 Chapter 8 Variation of urinary protein to creatinine ratio during the day 105 in women with suspected preeclampsia BJOG 2014, 121:13, 1660-5 Chapter 9 Differential diagnosis of preeclampsia: remember the soluble 115 fms-like tyrosine kinase 1/placental growth factor ratio Hypertension 2012, 60:4, 884-90 Chapter 10 sFlt-1 and PlGF measurements and their ratio for the diagnosis 129 and prognosis of preeclampsia in a high-risk cohort Submitted Chapter 11 A key role for endothelin-1 in the pathogenesis of 145 preeclampsia and the associated suppression of the renin-angiotensin-aldosterone system Hypertension, in press Chapter 12 Summary, discussion and perspectives 165 Chapter 1 General introduction and aims Chapter 1 General introduction Angiotensin II, the active end-product of the renin-angiotensin-aldosterone system (RAAS), exerts its effects via angiotensin II type 1 (AT1) and type 2 (AT2) receptors. AT1-receptors mediate all well-known effects of angiotensin II, such as vasoconstriction, sodium reten- tion, inflammation and tissue remodeling. Blockade of the RAAS, by inhibiting the forma- tion of angiotensin II or blocking the AT1-receptor, is very effective in the treatment of cardiovascular disease. AT2-receptors are believed to counteract the effects mediated by the AT1-receptor. Therefore, stimulation of this receptor may be an interesting target for the treatment of cardiovascular disease. C21 is a selective AT2-receptor agonist, recently developed aiming to treat cardiovascular disease. However, the general view that AT2-receptors exclusively exert beneficial effects has been challenged. For example in pathological models, their function sometimes mimics that of AT1-receptors, inducing vasoconstriction and cardiac hypertrophy.1, 2 Yet, given its upre- gulation in various pathological conditions, the AT2-receptor remains a promising target for treatment, allowing effects beyond blood pressure-lowering, for example in stroke, reducing aneurysm formation,3, 4 inflammation and myocardial fibrosis. Recent interest has focused on the presence of renin and angiotensinogen in urine, as markers of RAAS activity within the kidney. Indeed, if the renal levels of both proteins reflect their production at renal tissue sites, their measurement would be a simple tool to determine whether the renal RAS is upregulated, thereby reinforcing the need for (more intensive) treatment with a RAS blocker. Obviously, before drawing this conclusion, we need to be certain that these urinary proteins, like albumin, do not simply reflect break- down of the glomerular filtration barrier, i.e., that they are kidney- and not plasma-de- rived. If plasma-derived, their clinical value on top of a much cheaper urinary albumin measurement remains questionable. Pregnancy demands major changes of the cardiovascular system, and this involves, among others, activation of the RAAS, allowing an aldosterone-dependent increase in the -ex tracellular volume compartment. Remarkably, a relative resistance to the angiotensin II pressor response develops simultaneously to prevent the increase in blood pressure that normally is a result of RAAS activation when extracellular volume is increased. The increase in volume, the degree of RAAS activation and the diminished pressor response to angiotensin II are less pronounced in preeclampsia, a pregnancy-associated condition of elevated blood pressure and proteinuria. In animal models displaying excessive RAAS activation a preeclampsia-like syndrome develops during pregnancy, and in this situation the aldosterone/renin ratio is elevated compared to normal pregnancy. 8 General introduction and aims Chapter Whether the RAAS plays a role in the pathophysiology of preeclampsia or whether it is just an epiphenomenon has still to be elucidated. New insights into the pathogenesis of preeclampsia have revealed a major role for vascular 1 endothelial growth factor (VEGF), the soluble VEGF-type 1 receptor inhibitor sFlt-1, and low levels of placental growth factor (PlGF, a member of the VEGF family). The ratio of sFlt-1 and PlGF has shown to be increased in preeclampsia. Whether this ratio can be utili- zed as a predictor for preeclampsia or its complications is under investigation.5 Aims of the thesis In Part 1 the function of the AT2-receptor in health and disease is discussed as well as the therapeutic potential of a novel agonist for this receptor. The aim of Chapter 2 is to summarize the evidence that the AT2-receptor truly antagonizes AT1-receptor-mediated effects and what the role of the AT2-receptor is in diseased states. Chapter 3 aims to clarify contradicting findings about the function of C21, a selective AT2-receptor agonist. While investigating the role of the RAAS in normal pregnancy and pregnancy complicated by preeclampsia, we also aimed to find out whether the function of the AT2-receptor changes in preeclampsia (Chapter 11). In Part 2 we investigate the use of RAAS components in urine as potential markers for intrarenal RAAS activity. In Chapter 4 we summarize currently known evidence about the existence of a local RAAS in the kidney and we aim to find components in urine that could be a proxy for this activity. Chapter 5 compares a novel method to measure renin with established methods of renin measurement in diverse body fluids both under physiological and pathological conditions. Part 3 of this thesis covers recent developments about the role of angiogenic imbalance in the pathogenesis of preeclampsia, and the value of the sFlt-1/PlGF ratio as a biomarker to diagnose preeclampsia and to predict its prognosis. Chapter 6 summarizes recent findings in the pathogenesis of preeclampsia. The aim of chapter 7 is to provide an over- view of the effects of a disturbed angiogenic balance in preeclampsia and how this relates to the well-known adaptations of the RAAS observed in this condition. The quantification of proteinuria is still a cornerstone in the diagnosis of preeclampsia. In chapter 8 we compare the much easier to use protein-to-creatinine ratio with the 24- hour urinary protein measurement in diagnosing clinically relevant proteinuria in patients suspected of preeclampsia. 9 Chapter 1 In chapter 9 we investigate the usefulness of the sFlt-1/PlGF ratio biomarker for distin- guishing preeclampsia from other causes of hypertensive and proteinuric disease during pregnancy. The use of this ratio for the diagnosis of preeclampsia is further explored in chapter 10, where this test is applied in a high-risk patient cohort. Chapter 11 aims to investigate the consequences of a disturbed angiogenic balance on the systemic RAAS. Additionally we investigated if an activated renal RAAS is present in preeclamptic women and whether this is reflected by components of the RAAS in urine. REFERENCES 1. Moltzer E, Verkuil AV, van Veghel R, Danser AH and van Esch JH. Effects of angiotensin metabolites in the coronary vascular bed of the spontaneously hypertensive rat: loss of angiotensin II type 2 receptor-mediated vasodilation. Hypertension. 2010;55:516-22. 2. Pinaud F, Bocquet A, Dumont O, Retailleau K, Baufreton C, Andriantsitohaina R, Loufrani L and Henrion D. Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats. Hypertension. 2007;50:96- 102. 3. Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F, Bedja D, Chen Y, Modiri AN, Judge DP and Dietz HC. Angiotensin II
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