Advances in the pathophysiology of pre-eclampsia and related podocyte injury

Abstract

Pre-eclampsia is a pregnancy-specific hypertensive disorder that may lead to serious maternal and fetal complications. It is a multisystem disease that is commonly, but not always, accompanied by proteinuria. Its cause(s) remain unknown, and delivery remains the only definitive treatment. It is increasingly recognized that many pathophysiological processes contribute to this syndrome, with different signaling pathways converging at the point of systemic endothelial dysfunction, hypertension, and proteinuria. Different animal models of pre-eclampsia have proven utility for specific aspects of pre-eclampsia research, and offer insights into pathophysiology and treatment possibilities. Therapeutic interventions that specifically target these pathways may optimize pre-eclampsia management and may improve fetal and maternal outcomes. In addition, recent findings regarding placental, endothelial, and podocyte pathophysiology in pre-eclampsia provide unique and exciting possibilities for improved diagnostic accuracy. Emerging evidence suggests that testing for urinary podocytes or their markers may facilitate the prediction and diagnosis of pre-eclampsia. In this review, we explore recent research regarding placental, endothelial, and podocyte pathophysiology. We further discuss new signaling and genetic pathways that may contribute to pre-eclampsia pathophysiology, emerging screening and diagnostic strategies, and potential targeted interventions.

Figure 1. Etiologies and pathophysiology of pre-eclampsia

Several different signaling pathways may play a role, ultimately converging at the point of systemic endothelial dysfunction, hypertension, and proteinuria. Abbreviations: AT1-AA, autoantibodies to the angiotensin II type 1 receptor; AT1-AA-B2 heterodimers, angiotensin II type 1 receptor-bradykinin type 2 receptor heterodimers; carbon monoxide; CKD, chronic renal disease; CTD, connective tissue disease; DM, diabetes mellitus; HELLP, hemolysis, elevated liver enzymes, low platelet count; IL-6, interleukin 6; LFT, liver function tests; PlGF, placental growth factor; PRES, posterior reversible encephalopathy syndrome; sFlt-1, soluble fms-like tyrosine kinase 1; TNFα, tumor necrosis factor α; VEGF, vascular endothelial growth factor. * Reduced risk for pre-eclampsia

Figure 2. Regulation of nitric oxide (NO) synthesis

Left side: calcium-dependent, mediated by acetylcholine and bradykinin. Right side: calcium-independent, stimulated by vascular endothelial growth factor (VEGF). In pre-eclampsia, elevated levels of soluble fms-like tyrosine kinase 1 (sFlt-1) may act as a non-signaling decoy, thus interfering with VEGF-dependent phosphorylation/stimulation of endothelial NOS (eNOS). Abbreviations: Akt, protein kinase B; Arg, arginine; cGMP, cyclic guanosine monophosphate; DAG, diacylglycerol; ER, endoplasmic reticulum; G_q-P, phosphorylated G_q protein; IP₃, inositol triphosphate; PIP₂, phosphatidylinositol biphosphate; PLC, phospholipase C.

Figure 3. Possible mechanisms of the association between pre-eclampsia and future renal disease

Abbreviations: CKD, chronic kidney disease; ESRD, end-stage renal disease.