THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN THE PREGNANT RAT

Abstract

Objective: Preeclampsia is the leading cause of maternal and fetal morbidity and mortality in the United States, affecting ~2–5% of all pregnancies. Women with a history of preeclampsia have a 4-fold increased risk for developing hypertension, 2-fold increased risk for developing stroke, and 2-fold increased risk for developing ischemic heart disease later in life. Although it is known that intact renin-angiotensin-aldosterone system (RAAS) signaling is critical to a healthy pregnancy and that the RAAS is altered in preeclampsia the pathogenic mechanisms are largely unknown and a comprehensive examination of RAAS metabolism and receptor expression is lacking in the literature. The purpose of this study is to understand how the vasculature becomes refractory to the reported high circulating angiotensin II (ANGII) during pregnancy. This work provides basic information needed to understand blood pressure regulation and volume expansion in normal pregnancy, and why it fails to occur in women with preeclampsia, resulting in hypertension and fetal growth restriction. Design and method: We performed AT1 receptor autoradiography in kidneys of virgin (V) and late pregnant (LP) rats. We also performed equilibrium RAAS Fingerprinting in the plasma and kidneys of LP rats and V rats using a new LC/MS technique. Results: Using this new method, ANGII levels were decreased in the plasma and unchanged in the kidney of LP animals. This was surprising as it is inconsistent with historical data, however, other methods of measuring ANGII are problematic and often unreliable. There was a very high Aldosterone/ANGII-ratio (AA2) in both plasma and kidney of LP animals. The AA2-ratio provides information about the adrenal aldosterone-releasing response to ANGII. We also found that AT1R expression is decreased in the kidneys of LP compared to V rats. Conclusions: These results suggest a systemic down regulation of renal ANGII signaling with increased adrenal signaling. Continuing studies are assessing the RAAS signaling cascade to further validate these data, which may revolutionize the way we think about the RAAS in pregnancy, leading to improved treatment of women with preeclampsia.