Role of the renin-angiotensin system in the pathogenesis of preeclampsia

Abstract

Shah, Dinesh M. Role of the renin-angiotensin system in the pathogenesis of preeclampsia. Am J Physiol Renal Physiol 288: F614 -F625, 2005; doi:10.1152/ ajprenal.00410.2003.-Preeclampsia is a hypertensive disorder unique to pregnancy with consistent involvement of the kidney. The renin-angiotensin system (RAS) has been implicated in the pathogenesis of preeclampsia. In the gravid state, in addition to the RAS in the kidney, there is a tissue-based RAS in the uteroplacental unit. Increased renin expression observed both in human preeclampsia and in a transgenic mouse model with a human preeclampsia-like syndrome supports the concept that activation of the uteroplacental RAS, with angiotensin II entering the systemic circulation, may mediate the pathogenesis of preeclampsia. A novel disease paradigm of the two-kidney one-clip (2K-1C) Goldblatt model is presented for preeclampsia, wherein the gravid uterus is the clipped "kidney" and the two maternal kidneys represent the unclipped kidney. Validation of the 2K-1C Goldblatt model analogy requires evidence of elevated angiotensin II in the peripheral circulation before vascular maladaptation in preeclampsia. Convincing evidence of the elevation of angiotensin II in preeclampsia does not exist despite the fact that much of vascular pathogenesis appears to be due to angiotensin type I (AT 1) receptor activation. Vascular maladaptation with increased vasomotor tone, endothelial dysfunction, and increased sensitivity to angiotensin II and norepinephrine in manifest preeclampsia may be explained on the basis of angiotensin II-mediated mechanisms. Recently, novel angiotensin II-related biomolecular mechanisms have been described in preeclampsia. These include AT 1 and bradykinin B2 receptor heterodimerization and the production of an autoantibody against AT1. Various organ systems with a predilection for involvement in preeclampsia are each a site of a tissue-based RAS. How angiotensin II-mediated mechanisms may explain the primary clinical-pathological features of preeclampsia is described. Future investigations are proposed to more precisely define the role of activation of the uteroplacental RAS in the mechanisms underlying preeclampsia.HYPERTENSIVE DISORDERS COMPLICATE approximately 5-7% of all pregnancies (35a). These disorders include 1) chronic hypertension of whatever origin, including essential hypertension and chronic renal disease; 2) gestational hypertension, a hypertensive disorder occurring in pregnancy without multisystem involvement; 3) preeclampsia syndrome superimposed on chronic hypertension; 4) preeclampsia syndrome occurring de novo and only in the first pregnancy; and 5) preeclampsia syndrome occurring in a subsequent pregnancy and/or recurring with an underlying susceptibility state.Preeclampsia is a unique syndrome of pregnancy characterized by hypertension, proteinuria, and, frequently, edema. Several pathophysiological mechanisms have been implicated in the development of preeclampsia. These include endothelial dysfunction (36), an inflammatory p...

Vasoreactivity of Chorionic Plate Arteries in Response to Vasoconstrictors Produced by Preeclamptic Placentas

“…However, the impact of the altered RAS on the fetal side of the placenta is not well defined [41,42]. Most of the vasoactive effects of ANG II are produced depending on which angiotensin II receptor is expressed in the smooth muscle of the particular tissue of interest.…”

Recent Progress Toward the Understanding of the Pathophysiology of Hypertension During Preeclampsia

“…57,58 In contrast, during preeclampsia there appears to be a marked increase in the sensitivity to Ang II. 57,58 Although the mechanisms underlying these observations remain unclear, there is growing evidence to suggest that dysregulation of the tissuebased and circulating renin-angiotensin system (RAS) may be involved in the pathophysiology of preeclampsia.…”

“…57,58 In contrast, during preeclampsia there appears to be a marked increase in the sensitivity to Ang II. 57,58 Although the mechanisms underlying these observations remain unclear, there is growing evidence to suggest that dysregulation of the tissuebased and circulating renin-angiotensin system (RAS) may be involved in the pathophysiology of preeclampsia. [57][58][59][60][61] Recent studies in preeclamptic women demonstrate increased circulating concentrations of an agonistic autoantibody to the angiotensin type 1 receptor (AT1-AA).…”

“…57,58 Although the mechanisms underlying these observations remain unclear, there is growing evidence to suggest that dysregulation of the tissuebased and circulating renin-angiotensin system (RAS) may be involved in the pathophysiology of preeclampsia. [57][58][59][60][61] Recent studies in preeclamptic women demonstrate increased circulating concentrations of an agonistic autoantibody to the angiotensin type 1 receptor (AT1-AA). 58,62 In addition to being elevated during preeclampsia, the AT1-AA has also been reported to be increased in postpartum women.…”

Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia

“…11 A tissue-based RAS has been described in the uteroplacental unit in the gravid state. 12 For this study, we selected only women undergoing cesarean section so that the tissues would not be perturbed. We separately investigated the 2 types of tissues from the uteroplacental unit (decidua and placenta) in the same pregnant women with or without preeclampsia.…”