Review article

The renin–angiotensin–aldosterone system in pre-eclampsia: the delicate balance between good and bad

Koen Verdonk, Willy Visser, Anton H. Van Den Meiracker, A. H. Jan Danser


Pregnancy demands major changes of the cardiovascular system, and this involves, among others, activation of the RAAS (renin–angiotensin–aldosterone system), allowing an aldosterone-dependent increase in volume. Remarkably, a relative resistance to the pressor response of AngII (angiotensin II) develops simultaneously to prevent the increase in blood pressure that would normally accompany RAAS activation. The increase in volume, the degree of RAAS activation and the diminished pressor response to AngII are less pronounced in pre-eclampsia. However, animal models displaying excessive RAAS activation also result in a pre-eclampsia-like syndrome, and the aldosterone/renin ratio is elevated in pre-eclampsia compared with a normal pregnancy. New insights into the pathogenesis of pre-eclampsia have revealed a major role for VEGF (vascular endothelial growth factor), VEGF-inactivating sFlt-1 (soluble fms-like tyrosine kinase-1) and AT1 (angiotensin II type 1) receptor autoantibodies. The last mentioned activate AT1 receptors, thereby potentially suppressing circulating renin and aldosterone. VEGF, both directly and indirectly (by increasing capillary density), affects adrenal aldosterone synthesis. The present review summarizes all of the recent findings regarding RAAS regulation in pre-eclampsia compared with normal pregnancy, concluding that factors such as sFlt-1 and AT1 receptor autoantibodies disturb the delicate balance that normally results in a volume increase and a diminished vasoconstrictor response to AngII in pregnant women. It is possible that there are non-parallel changes in the circulating and renal RAAS in pre-eclampsia, which are potentially reflected by the urinary levels of renin.

  • aldosterone
  • autoantibody
  • pre-eclampsia
  • prorenin
  • renin
  • renin–angiotensin–aldosterone system (RAAS)
  • soluble fms-like tyrosine kinase-1 (sFlt-1)
  • vascular endothelial growth factor (VEGF)

Abbreviations: ACE2, angiotensin-converting enzyme 2; Ang-(1–7), angiotensin-(1–7); AngII, angiotensin II; AT1 receptor, AngII type 1 receptor; AT1-AA, agonistic autoantibody against AT1 receptor; AT2 receptor, AngII type 2 receptor; ET-1, endothelin-1; PAI-1, plasminogen-activator inhibitor-1; PlGF, placental growth factor; PRA, plasma renin activity; proMBP, proform of eosinophil major basic protein; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; sFlt-1, soluble fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factor

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