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

Craici IM, Wagner SJ, Weissgerber TL, Grande JP, Garovic VD - Kidney Int. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, University of Mississippi Medical Center, Jackson, Mississippi, USA.

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.

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Etiologies and pathophysiology of pre-eclampsiaSeveral 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
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Figure 1: Etiologies and pathophysiology of pre-eclampsiaSeveral 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

Mentions: The prediction and treatment of preeclampsia is complicated by the fact that many pathophysiological processes may contribute to this syndrome. These causal pathways are believed to converge at the point of systemic endothelial dysfunction, which leads to hypertension and proteinuria (Figure 1). The fact that hypertension rapidly resolves upon the removal of the fetus and placenta has led to several theories implicating structural and/or functional changes in the developing placenta as factors causing pre-eclampsia. Placental hypoxia is frequently viewed as an early event that may cause placental production of soluble factors leading to endothelial dysfunction.11 Over the last decade, pre-eclampsia has been associated with elevated levels of the soluble receptor for vascular endothelial growth factor (VEGF) of placental origin. This soluble receptor, commonly referred to as soluble fms-like tyrosine kinase receptor-1 (sFlt-1), may bind and neutralize VEGF, and thus limit the availability of free VEGF for fetal and placental angiogenesis. Several rodent models simulate pre-eclampsia by exogenous sFlt-1 administration. In the most direct model, intraperitoneal sFlt-1 injections produce short-term elevations of sFlt-1.12 In the hours after sFlt-1 injection, animals develop hypertension, proteinuria, and altered podocyte protein expression, but do not develop glomerular endotheliosis, the classical renal lesion of pre-eclampsia. Administration of an adenoviral vector encoding sFlt-1 leads to longer-term sFlt-1 exposure in rats.13 This model reproduces the findings of hypertension, proteinuria, and glomerular endotheliosis. Elevated levels of another anti-angiogenic factor, soluble endoglin, have been subsequently implicated in neutralizing transforming factor-β and the resultant vascular damage in pre-eclampsia and HELLP syndrome.14 These anti-angiogenic factors are commonly viewed as the missing link between abnormal placentation and the maternal syndrome. However, these factors are likely a consequence, rather than the cause, of placental ischemia in pre-eclampsia. As such, they likely play an important role in “placental” pre-eclampsia, in which placental ischemia is present, but not in “maternal” pre-eclampsia, which occurs in the absence of placental ischemia,7 or in postpartum pre-eclampsia15 which occurs after delivery in the absence of the placenta.


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

Craici IM, Wagner SJ, Weissgerber TL, Grande JP, Garovic VD - Kidney Int. (2014)

Etiologies and pathophysiology of pre-eclampsiaSeveral 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
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4117806&req=5

Figure 1: Etiologies and pathophysiology of pre-eclampsiaSeveral 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
Mentions: The prediction and treatment of preeclampsia is complicated by the fact that many pathophysiological processes may contribute to this syndrome. These causal pathways are believed to converge at the point of systemic endothelial dysfunction, which leads to hypertension and proteinuria (Figure 1). The fact that hypertension rapidly resolves upon the removal of the fetus and placenta has led to several theories implicating structural and/or functional changes in the developing placenta as factors causing pre-eclampsia. Placental hypoxia is frequently viewed as an early event that may cause placental production of soluble factors leading to endothelial dysfunction.11 Over the last decade, pre-eclampsia has been associated with elevated levels of the soluble receptor for vascular endothelial growth factor (VEGF) of placental origin. This soluble receptor, commonly referred to as soluble fms-like tyrosine kinase receptor-1 (sFlt-1), may bind and neutralize VEGF, and thus limit the availability of free VEGF for fetal and placental angiogenesis. Several rodent models simulate pre-eclampsia by exogenous sFlt-1 administration. In the most direct model, intraperitoneal sFlt-1 injections produce short-term elevations of sFlt-1.12 In the hours after sFlt-1 injection, animals develop hypertension, proteinuria, and altered podocyte protein expression, but do not develop glomerular endotheliosis, the classical renal lesion of pre-eclampsia. Administration of an adenoviral vector encoding sFlt-1 leads to longer-term sFlt-1 exposure in rats.13 This model reproduces the findings of hypertension, proteinuria, and glomerular endotheliosis. Elevated levels of another anti-angiogenic factor, soluble endoglin, have been subsequently implicated in neutralizing transforming factor-β and the resultant vascular damage in pre-eclampsia and HELLP syndrome.14 These anti-angiogenic factors are commonly viewed as the missing link between abnormal placentation and the maternal syndrome. However, these factors are likely a consequence, rather than the cause, of placental ischemia in pre-eclampsia. As such, they likely play an important role in “placental” pre-eclampsia, in which placental ischemia is present, but not in “maternal” pre-eclampsia, which occurs in the absence of placental ischemia,7 or in postpartum pre-eclampsia15 which occurs after delivery in the absence of the placenta.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, University of Mississippi Medical Center, Jackson, Mississippi, USA.

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.

Show MeSH
Related in: MedlinePlus