Elsevier

Seminars in Nephrology

Volume 31, Issue 1, January 2011, Pages 47-58
Seminars in Nephrology

Renin Angiotensin Signaling in Normal Pregnancy and Preeclampsia

https://doi.org/10.1016/j.semnephrol.2010.10.005Get rights and content

Summary

Many reports indicate that there is an increase in almost all of the components of the renin-angiotensin system (RAS) during an uncomplicated pregnancy, but renin activity, angiotensin II, and aldosterone decrease in preeclampsia (PE) for reasons that are unclear. PE is a life-threatening disorder of late pregnancy characterized by hypertension, proteinuria, increased soluble fms-like tyrosine kinase-1, as well as renal and placental morphologic abnormalities. Although a leading cause of maternal and perinatal morbidity and mortality, the pathogenic mechanisms of PE remain largely undefined. Immunologic mechanisms and aberrations of the RAS have been long considered contributors to the disorder. Bridging these two concepts, numerous studies report the presence of the angiotensin II type I receptor agonistic autoantibody (AT1-AA) found circulating in preeclamptic women. This autoantibody induces many key features of the disorder through AT1 receptor signaling, and has been implicated in the pathogenesis of PE. Here we review the functions of the RAS during normal pregnancy and PE, and highlight the role of AT1-AA in both animal models and in the human disorder.

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

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