Abstract
Circulating aldosterone levels are increased in human pregnancy. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity. Moreover, inactivating polymorphisms in the aldosterone synthase gene have been detected in preeclamptic women. Here, we used aldosterone synthase-deficient (AS−/−) mice to test whether the absence of aldosterone is sufficient to impair pregnancy or even to cause preeclampsia. AS−/− and AS+/+ females were mated with AS+/+ and AS−/− males, respectively, always generating AS+/− offspring. With maternal aldosterone deficiency in AS−/− mice, systolic blood pressure was low before and further reduced during pregnancy with no increase in proteinuria. Yet, AS−/− had smaller litters due to loss of fetuses as indicated by a high number of necrotic placentas with massive lymphocyte infiltrations at gestational day 18. Surviving fetuses and their placentas from AS−/− females were smaller. High-salt diet before and during pregnancy increased systolic blood pressure only before pregnancy in both genotypes and abolished the difference in blood pressure during late pregnancy. Litter size from AS−/− was slightly improved and the differences in placental and fetal weights between AS+/+ and AS−/− mothers disappeared. Overall, an increased placental efficiency was observed in both groups paralleled by a normalization of elevated HIF1α levels in the AS−/− placentas. Our results demonstrate that aldosterone deficiency has profound adverse effects on placental function. High dietary salt intake improved placental function. In this animal model, aldosterone deficiency did not cause preeclampsia.
Similar content being viewed by others
References
Adelman DM, Gertsenstein M, Nagy A, Simon MC, Maltepe E (2000) Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev 14:3191–3203
Alexander BT (2003) Placental insufficiency leads to development of hypertension in growth-restricted offspring. Hypertension 41:457–462
Booth RE, Johnson JP, Stockand JD (2002) Aldosterone. Adv Physiol Educ 26:8–20
Burke SD, Barrette VF, Bianco J, Thorne JG, Yamada AT, Pang SC, Adams MA, Croy BA (2010) Spiral arterial remodeling is not essential for normal blood pressure regulation in pregnant mice. Hypertension 55:729–737
Chapman AB, Abraham WT, Zamudio S, Coffin C, Merouani A, Young D, Johnson A, Osorio F, Goldberg C, Moore LG, Dahms T, Schrier RW (1998) Temporal relationships between hormonal and hemodynamic changes in early human pregnancy. Kidney Int 54:2056–2063
Dahlstrom B, Romundstad P, Oian P, Vatten LJ, Eskild A (2008) Placenta weight in pre-eclampsia. Acta Obstet Gynecol Scand 87:608–611
Duley L, Henderson-Smart D, Meher S (2005) Altered dietary salt for preventing pre-eclampsia, and its complications. Cochrane Database Syst Rev. doi:10.1002/14651858.CD005548, Issue 4, Art. No. CD005548
Escher G, Mohaupt M (2007) Role of aldosterone availability in preeclampsia. Mol Asp Med 28:245–254
Escher G, Cristiano M, Causevic M, Baumann M, Frey FJ, Surbek D, Mohaupt MG (2009) High aldosterone-to-renin variants of CYP11B2 and pregnancy outcome. Nephrol Dial Transplant 24:1870–1875
Farese S, Shojaati K, Kadereit B, Frey FJ, Mohaupt MG (2006) Blood pressure reduction in pregnancy by sodium chloride. Nephrol Dial Transplant 21:1984–1987
Fowden AL, Sferruzzi-Perri AN, Coan PM, Constancia M, Burton GJ (2009) Placental efficiency and adaptation: endocrine regulation. J Physiol 587:3459–3472
Gallery ED (1982) Pregnancy-associated hypertension: interrelationships of volume and blood pressure changes. Clin Exp Hypertens B 1:39–47
Gallery ED, Brown MA (1987) Control of sodium excretion in human pregnancy. Am J Kidney Dis 9:290–295
Gallery ED, Hunyor SN, Gyory AZ (1979) Plasma volume contraction: a significant factor in both pregnancy-associated hypertension (pre-eclampsia) and chronic hypertension in pregnancy. Q J Med 48:593–602
Genbacev O, Zhou Y, Ludlow JW, Fisher SJ (1997) Regulation of human placental development by oxygen tension. Science 277:1669–1672
Gennari-Moser C, Khankin EV, Schuller S, Escher G, Frey BM, Portmann CB, Baumann MU, Lehmann AD, Surbek D, Karumanchi SA, Frey FJ, Mohaupt MG (2011) Regulation of placental growth by aldosterone and cortisol. Endocrinology 152:263–271
Hays PM, Cruikshank DP, Dunn LJ (1985) Plasma volume determination in normal and preeclamptic pregnancies. Am J Obstet Gynecol 151:958–966
Huang ST, Vo KC, Lyell DJ, Faessen GH, Tulac S, Tibshirani R, Giaccia AJ, Giudice LC (2004) Developmental response to hypoxia. FASEB J 18:1348–1365
Jensen E, Wood CE, Keller-Wood M (2007) Reduction of maternal adrenal steroids results in increased VEGF protein without increased eNOS in the ovine placenta. Placenta 28:658–667
Krege JH, Hodgin JB, Hagaman JR, Smithies O (1995) A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension 25:1111–1115. doi:10.1161/01.HYP.25.5.1111
Lee G, Makhanova N, Caron K, Lopez ML, Gomez RA, Smithies O, Kim HS (2005) Homeostatic responses in the adrenal cortex to the absence of aldosterone in mice. Endocrinology 146:2650–2656
Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683
Makhanova N, Lee G, Takahashi N, Sequeira Lopez ML, Gomez RA, Kim HS, Smithies O (2006) Kidney function in mice lacking aldosterone. Am J Physiol Renal Physiol 290:F61–F69
Makhanova N, Sequeira-Lopez ML, Gomez RA, Kim HS, Smithies O (2006) Disturbed homeostasis in sodium-restricted mice heterozygous and homozygous for aldosterone synthase gene disruption. Hypertension 48:1151–1159
Moffett-King A (2002) Natural killer cells and pregnancy. Nat Rev Immunol 2:656–663
Nicod J, Bruhin D, Auer L, Vogt B, Frey FJ, Ferrari P (2003) A biallelic gene polymorphism of CYP11B2 predicts increased aldosterone to renin ratio in selected hypertensive patients. J Clin Endocrinol Metab 88:2495–2500
Nolten WE, Lindheimer MD, Oparil S, Ehrlich EN (1978) Desoxycorticosterone in normal pregnancy. I. Sequential studies of the secretory patterns of desoxycorticosterone, aldosterone, and cortisol. Am J Obstet Gynecol 132:414–420
Noris M, Perico N, Remuzzi G (2005) Mechanisms of disease: pre-eclampsia. Nat Clin Pract Nephrol 1:98–114, quiz 120
Parikh SM, Karumanchi SA (2008) Putting pressure on pre-eclampsia. Nat Med 14:810–812
Pascoe L, Curnow KM, Slutsker L, Rosler A, White PC (1992) Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Proc Natl Acad Sci U S A 89:4996–5000
Puschett JB (2006) The role of excessive volume expansion in the pathogenesis of preeclampsia. Med Hypotheses 67:1125–1132
Robinson M (1958) Salt in pregnancy. Lancet 1:178–181
Salas SP, Marshall G, Gutierrez BL, Rosso P (2006) Time course of maternal plasma volume and hormonal changes in women with preeclampsia or fetal growth restriction. Hypertension 47:203–208
Seaton B, Ali A (1984) Simplified manual high performance clinical chemistry methods for developing countries. Med Lab Sci 41:327–336
Shojaati K, Causevic M, Kadereit B, Dick B, Imobersteg J, Schneider H, Beinder E, Kashiwagi M, Frey BM, Frey FJ, Mohaupt MG (2004) Evidence for compromised aldosterone synthase enzyme activity in preeclampsia. Kidney Int 66:2322–2328
Sohn HJ, Yoo KH, Jang GY, Lee JH, Choi BM, Bae IS, Yim HE, Son CS, Lee JW (2010) Aldosterone modulates cell proliferation and apoptosis in the neonatal rat heart. J Korean Med Sci 25:1296–1304
Symonds EM, Broughton Pipkin F, Craven DJ (1975) Changes in the renin-angiotensin system in primigravidae with hypertensive disease of pregnancy. Br J Obstet Gynaecol 82:643–650
Wacker J, Piel P, Lewicka S, Haack D, Vecsei P, Bastert G (1995) Increased aldosterone-18-glucuronide/tetrahydroaldosterone ratios in pregnancy. Endocr Res 21:197–202
Yim HE, Yoo KH, Bae IS, Jang GY, Hong YS, Lee JW (2009) Aldosterone regulates cellular turnover and mitogen-activated protein kinase family expression in the neonatal rat kidney. J Cell Physiol 219:724–733
Young BC, Levine RJ, Karumanchi SA (2010) Pathogenesis of preeclampsia. Annu Rev Pathol 5:173–192
Acknowledgments
We gratefully acknowledge the technical support by the Zurich Integrative Rodent Physiology (ZIRP) facility. We thank Charlotte Burger for expert technical help with tissue processing and slide scanning. Imaging was performed with equipment maintained by the Center for Microscopy and Image Analysis, University of Zurich. This study was supported by a collaborative project grant by the Zurich Center for Integrative Human Physiology (ZIHP) to J. Loffing and C.A. Wagner. The laboratories of J. Loffing and C.A. Wagner are also supported by independent project grants from the Swiss National Science Foundation (JL: 310030-122243; CAW: 31003A_138143/1) and by funds from the Swiss National Centre of Competence in Research “Kidney.CH”. M. Mohaupt was supported by the Swiss National Science Foundation by an independent project grant (3200030_135596/1) and also by funds from the Swiss National Centre of Competence in Research “Kidney.CH”.
Author information
Authors and Affiliations
Corresponding author
Additional information
J. Loffing and C.A. Wagner contributed equally to this work and share last authorship
Rights and permissions
About this article
Cite this article
Todkar, A., Di Chiara, M., Loffing-Cueni, D. et al. Aldosterone deficiency adversely affects pregnancy outcome in mice. Pflugers Arch - Eur J Physiol 464, 331–343 (2012). https://doi.org/10.1007/s00424-012-1145-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-012-1145-4