Renin Angiotensin Signaling in Normal Pregnancy and Preeclampsia
Section snippets
Uncomplicated Pregnancies Require Regulation of the RAS
During an uncomplicated pregnancy, the RAS undergoes specific changes. The up-regulation of renin is the first change to occur, mainly owing to the extrarenal release locally by the ovaries and maternal decidua.7 As it grows, the placenta produces estrogen, a steroid hormone vital to sustain pregnancy. Estrogen also increases angiotensinogen synthesis by the liver, leading to increased serum ANG II.8 The only RAS component that is reported to decrease during normal pregnancy is ACE.9, 10, 11
Dysregulation of the RAS in Preeclamptic Women
Preeclampsia (PE) is a disorder of pregnancy characterized by hypertension and proteinuria. This life-threatening condition affects approximately 7% of pregnancies and results in substantial maternal and neonatal morbidity and mortality, and is therefore a major health concern.24 In its advanced and severe form, the clinical symptoms of PE may include cerebral edema, renal failure, and the hemolysis, elevated liver enzymes, and low platelets syndrome. Treatment for PE is hampered by the lack of
In Vivo Studies of the RAS and Hypertensive Disorders of Pregnancy
Animal models have contributed greatly to our understanding of the cellular interplay at the vascular level in women with PE because such models permit scrutiny of alterations in the RAS in multiple cell types. The use of rodent models is especially relevant because the RAS of rodents and human beings are remarkably similar. The mouse has two pharmacologically identical isotypes of the AT1 receptor, AT1a and AT1b.34, 35 Human beings have a single AT1-receptor isotype. In general, both human
A Source of Excess AT1-Receptor Activation: The Angiotensin II Type I Receptor Agonistic Autoantibody
Although the altered regulation of the RAS in PE is largely accepted, the reasons for these alterations are yet to be identified. Although ANG II levels are reportedly decreased in preeclamptic women as compared with normotensive pregnant women,16, 30 these patients show symptoms that could be attributed to excess AT1-receptor activation, such as hypertension and renal dysfunction. Again, the exact cause of this excess activation remains elusive. However, the discovery by Wallukat et al39 that
Animal Models and the Role of AT1-AA in the Maternal and Fetal Features of PE
Most of the evidence presented earlier was performed in vitro. To fully understand the role and pathogenic capabilities of the autoantibody, in vivo animal studies must be performed. Described here are the animal models that show the possible contributions and relationships of AT1-AA to both the maternal and fetal features observed in PE.
AT1-AA: Prevalence, Persistence, and the Push Forward
The exact etiology of self-recognizing antibodies in autoimmune diseases is difficult to discern. Many factors have been proposed that may lead to autoantibody production in general, including genetic predispositions, maladaptive immune responses, and environmental triggers.77, 78, 79 All of these mechanisms could contribute to the generation of the autoantibody associated with PE. It is currently unknown what triggers the production of AT1-AA and when the autoantibody first arises in
Conclusions and Significance
The RAS is altered in gestation, suggesting a crucial role in maintaining a normal pregnancy. It also is possible that failure to achieve the adaptations seen in an uncomplicated gestation contributes to the pathophysiology of PE. Although the RAS is generally up-regulated in an uncomplicated, normotensive pregnancy, this balance is lost in PE. The exact cause of this disequilibrium remains undetermined and requires further investigation.
One possible contributor to the aberrant RAS in PE is the
References (92)
- et al.
Physiological and pharmacological implications of AT1 versus AT2 receptors
Kidney Int
(1998) The human placental renin-angiotensin system
Front Neuroendocrinol
(1998)- et al.
Sodium excretion in normal and hypertensive pregnancy: a prospective study
Am J Obstet Gynecol
(1988) - et al.
Physiologic changes in pregnancy
Surg Clin North Am
(2008) - et al.
Plasma active renin, angiotensin I, and angiotensin II during pregnancy and in preeclampsia
Obstet Gynecol
(1998) Pressor response to angiotensin in pregnant and non-pregnant women
Am J Obstet Gynecol
(1961)- et al.
Control of vascular responsiveness during human pregnancy
Kidney Int
(1980) - et al.
Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human mesangial cells and induce interleukin-6 and plasminogen activator inhibitor-1 secretion
Am J Hypertens
(2005) - et al.
AT1 receptor heterodimers and angiotensin II responsiveness in preeclampsia
Semin Nephrol
(2004) - et al.
Preeclampsia: an endothelial cell disorder
Am J Obstet Gynecol
(1989)
Placental ischemia and soluble fms-like tyrosine kinase 1: cause or consequence of preeclampsia?
Kidney Int
Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR
Biochem Biophys Res Commun
Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome
Am J Pathol
Angiotensin II inhibits human trophoblast invasion through AT1 receptor activation
J Biol Chem
Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo
Kidney Int
The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis
Am J Kidney Dis
Morphometric analysis of pre-eclampsia in women biopsied in pregnancy and post-partum
Kidney Int
Lymphocyte intracellular free calcium concentration is increased in preeclampsia
Am J Obstet Gynecol
Calcium metabolism in pre-eclampsia
Int J Gynaecol Obstet
Erythrocyte cation metabolism in preeclampsia
Am J Obstet Gynecol
Agonistic AT(1) receptor autoantibodies and monocyte stimulation in hypertensive patients
Am J Hypertens
Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia
Am J Obstet Gynecol
Impaired placental neovascularization in mice with pregnancy-associated hypertension
Lab Invest
Genetic progress towards the molecular basis of autoimmunity
Trends Mol Med
The immune system and happiness
Autoimmun Rev
Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births
Lancet
Thrombomodulin, plasminogen activator inhibitor type 1 (PAI-1) and fibronectin as biomarkers of endothelial damage in preeclampsia and eclampsia
Int J Gynaecol Obstet
Prostaglandins stimulate renin secretion and renin mRNA in mouse renal juxtaglomerular cells
Am J Physiol
Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney
Hypertension
Apoptotic cascade initiated by angiotensin II in neonatal cardiomyocytes: role of DNA damage
Am J Physiol Heart Circ Physiol
The uteroplacental renin-angiotensin system: a review
Exp Clin Endocrinol
Changes in active and inactive renin throughout pregnancy
J Clin Endocrinol Metab
Angiotensin-(1-7) in normal and preeclamptic pregnancy
Endocrine
Angiotensin-converting enzyme and the renin-angiotensin system in normotensive primigravid pregnancy
Clin Exp Hypertens B
A prospective study of plasma angiotensin-converting enzyme in normotensive primigravidae and their infants
Br J Obstet Gynaecol
Regional flow-pressure relationship in response to angiotensin in the intact dog and sheep
Circ Res
Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness
Nat Med
Angiotensin II decreases system A amino acid transporter activity in human placental villous fragments through AT1 receptor activation
Am J Physiol Endocrinol Metab
Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy
Circ Res
Autoantibody from women with preeclampsia induces soluble fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling
Hypertension
Angiotensin receptor agonistic autoantibody-mediated TNF-alpha induction contributes to increased soluble endoglin production in preeclampsia
Circulation
AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase
Circulation
Latest advances in understanding preeclampsia
Science
Endothelial dysfunction in preeclampsia
Semin Reprod Endocrinol
Changes in the renin-angiotensin system in primigravidae with hypertensive disease of pregnancy
Br J Obstet Gynaecol
Renin-aldosterone relationships in pregnancy-induced hypertension
Am J Hypertens
Cited by (103)
Renin-angiotensin system in normal pregnancy and in preeclampsia: A comprehensive review
2022, Pregnancy HypertensionModelling female physiology from head to Toe: Impact of sex hormones, menstrual cycle, and pregnancy
2022, Journal of Theoretical BiologyCitation Excerpt :Indeed, healthy pregnancies are accompanied by an increase in heart rate, plasma volume, and cardiac output (Ganzevoort et al., 2004). Moreover, there is an increase in nearly all elements of the systemic RAS (Irani and Xia, 2011; Pepin É et al., 2017; Langer et al., 1998; Yang et al., 2013), ACE being the only exception (Pepin É et al., 2017; Oats et al., 1982; Merrill et al., 2002; Yang et al., 2013). Notably, the utero-placental unit develops a fully functioning RAS during pregnancy (Yang et al., 2013; Pepin É et al., 2017; Irani and Xia, 2008; Li et al., 1998; Shaw et al., 1989), though the functional role of this local system remains generally unknown.
Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia
2022, American Journal of Obstetrics and GynecologyActive plasma renin concentration throughout healthy and complicated pregnancy: a systematic review and meta-analysis
2024, Reproductive Biology and Endocrinology