27 The reduced plasma volume may be explained by the capillary leak syndrome and volume redistribution into the extracellular space, as there is no reduction in extracellular fluid volume.28 Therefore, the elevation in blood pressure may be more closely related to endothelial dysfunction and later, vasoconstriction rather than any direct effect of the RAAS.11 Alternative locally vasoactive compounds such as endothelin, nitric oxide inhibition, oxidative stress or cytokines have been implicated as vasoconstrictors in preeclampsia but selleck compound are not proven.29 The use

of antioxidants in humans has not been shown to treat or prevent preeclampsia.30 Interest in the endothelial cell integrity provided by angiogenic factor vascular VEGF (vascular endothelial growth factor) in pregnancy and its potential role in preeclampsia are not new.31,32 There was a resurgence in interest in angiogenic molecules after the elegant demonstration of a mechanistic role for the soluble VEGF receptor, soluble fms-like tyrosine kinase-1 (sFLT-1)33 in preeclampsia. The infusion of sFLT-1 in pregnant rodents induced

CHIR-99021 cost hypertension and proteinuria in pregnancy. The pathological feature of renal biopsies in this model is endothelial disruption similar to that seen in human preeclampsia. The same renal lesion, however, was seen in non-pregnant animals, thus providing evidence of direct renal toxic effect of sFLT-1. The specificity of this pathological mechanism in pregnancy rests with the placenta as the likely site of production. Zhao et al. have demonstrated a net increase in sFLT-1 binding in human renal tissue in preeclampsia.34 We and others have shown that the likely source of the sFLT-1 is acute placental ischaemia35,36 and that the effect of ischaemia and sFLT-1 on the renal capillary loops mimic those seen in human de novo disease (Fig. 1). The clinical importance of the increased sFLT-1 in humans

was demonstrated subsequently GNE-0877 in a longitudinal retrospective study. It was found that the maternal circulating sFLT-1 was significantly increased in women who were to develop preeclampsia later in the pregnancy. The elevation in sFLT-1 was noted about 5–6 weeks prior to the onset of clinically apparent disease.37 The correlation of high sFLT and low binding proteins VEGF and its co-agonist placental growth factor (PlGF) confirm the binding activity of the sFLT-1. The relative reduction in free VEGF (resultant from the increased sFLT-1) has a potentially important role in mediating the renal involvement in preeclampsia as outlined above. Other recently identified toxins in preeclampsia such as soluble endoglin38 do not appear to be a direct glomerular cell toxins,39 at least in animal studies where its effect is most potent in the presence of sFLT-1.