Preeclampsia is a pregnancy-specific disorder clinically characterized by hypertension and proteinuria that occurs after 20 weeks of gestation. The etiology and pathogenesis of this condition remain elusive, resulting in a failure to develop specific preventive and treatment strategies. Recent studies have provided evidence that preeclampsia is associated with elevated levels of the soluble receptor for vascular endothelial growth factor (VEGF). This soluble receptor, commonly referred to as sFlt-1 (from fmslike tyrosine kinase receptor-1), may bind and neutralize VEGF and thus decrease free VEGF levels that are required for active angiogenesis in pregnancy. We postulate that low free VEGF levels may contribute to the pathogenesis of preeclampsia in a dual fashion by causing: i) endothelial dysfunction and ii) glomerular epithelial cell (podocyte) dysregulation, leading to the two main clinical findings of preeclampsia, hypertension and proteinuria, respectively. We have demonstrated that nephrin, a slit diaphragm protein, is down-regulated in kidney sections of women who had severe preeclampsia compared to normal pregnancies. The slit diaphragm is a specialized cell-to-cell junction that connects neighboring podocytes and represents the main, size-selective filter in the kidney. In addition, we have shown that proteinuria in preeclampsia is associated with urinary loss of viable podocytes, i.e., podocyturia.
In Specific Aim 1, we will study the correlations among elevated levels of plasma sFlt-1 levels, down-regulation of slit diaphragm proteins (including nephrin), and podocyturia, and explore the role of podocyturia as a possible early marker for preeclampsia. We postulate that podocyturia may occur before proteinuria and preeclampsia develop. We also hypothesize that endothelial dysfunction, a hallmark of preeclampsia that leads to hypertension, is mediated in part by low free VEGF levels that may cause a decrease in endothelial nitric oxide synthase activity and nitric oxide production. This hypothesis will be tested in Specific Aim 2.
In Specific Aim 3, we will study the mechanisms by which defective VEGF signaling may down-regulate nephrin, disrupt the slit diaphragm, lead to podocyturia and, ultimately, proteinuria in preeclampsia. These studies will provide insights into basic mechanisms underlying the pathophysiology of preeclampsia, which are essential for developing more specific diagnostic and treatment approaches. Relevance: Preeclampsia affects 5% of pregnancies in the USA and remains one of the leading causes of both maternal and fetal morbidity and mortality. Currently, the only therapy is delivery, which frequently leads to premature birth and high neonatal morbidity. Development of more effective treatment strategies is critically dependent upon better understanding of underlying pathogenic mechanisms.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD051714-05
Application #
8236793
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Ilekis, John V
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$123,595
Indirect Cost
$9,155
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
White, Wendy M; Sun, Zhifu; Borowski, Kristi S et al. (2016) Preeclampsia/Eclampsia candidate genes show altered methylation in maternal leukocytes of preeclamptic women at the time of delivery. Hypertens Pregnancy 35:394-404
White, Wendy M; Garrett, Angelica T; Craici, Iasmina M et al. (2014) Persistent urinary podocyte loss following preeclampsia may reflect subclinical renal injury. PLoS One 9:e92693
Craici, Iasmina M; Wagner, Steven J; Weissgerber, Tracey L et al. (2014) Advances in the pathophysiology of pre-eclampsia and related podocyte injury. Kidney Int 86:275-85
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White, Wendy M; Brost, Brian; Sun, Zhifu et al. (2013) Genome-wide methylation profiling demonstrates hypermethylation in maternal leukocyte DNA in preeclamptic compared to normotensive pregnancies. Hypertens Pregnancy 32:257-69
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Weissgerber, Tracey L; Turner, Stephen T; Bailey, Kent R et al. (2013) Hypertension in pregnancy is a risk factor for peripheral arterial disease decades after pregnancy. Atherosclerosis 229:212-6
Craici, Iasmina M; Wagner, Steven J; Bailey, Kent R et al. (2013) Podocyturia predates proteinuria and clinical features of preeclampsia: longitudinal prospective study. Hypertension 61:1289-96

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