Our laboratory is characterizing final common disease pathways for vascular disorders, which will allow the development of novel diagnostics and therapeutics.
Preeclampsia is a pregnancy-specific hypertensive disorder characterized by new-onset hypertension and proteinuria and is associated with severe morbidity and mortality to the mother and the baby. The placenta is central to the pathogenesis of preeclampsia and is characterized by abnormal vascular remodeling of the spiral arterioles (Figure). We characterized sFlt1 (also referred to as sVEGFR1), an antagonist of circulating vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), from preeclamptic placentas and confirmed that it is released into the blood stream in vast excess in patients with preeclampsia.
Exogenous administration of sFlt1 into pregnant rats reproduces the phenotype of human preeclampsia, namely, proteinuria, hypertension, and glomerular endotheliosis, the classic histological renal lesion of preeclampsia. Work is in progress to understand the regulation of sFlt1 production by the cytotrophoblasts of the placenta. We are using our animal models to test the effects of antagonizing excess sFlt1 with growth factors and small molecules, with the goal of finding novel treatment options for this disease.
We are also characterizing other gene products that are elevated in preeclampsia (for example, soluble endoglin) and that may be synergistic to sFlt1 in the pathogenesis of preeclampsia and its related complications, such as the HELLP (hemolysis, elevated liver enzymes, low platelet) syndrome. Finally, we are evaluating the role of angiogenic proteins in the blood and urine of pregnant women for the prediction and diagnosis of preeclampsia.
Mechanisms of Proteinuria
Alterations of glomerular vascular permeability lead to proteinuria, one of the most common phenotypes of kidney disease. Our laboratory is interested in understanding the molecular mechanisms of proteinuria. Preliminary microarray data generated from glomerular podocytes grown in high and normal glucose (as a model for diabetic nephropathy) have revealed several novel targets and pathways. We are characterizing the novel gene products through in situ hybridization and immunohistochemisty in human kidney diseases. Newer in vitro assays to mimic in vivo proteinuria are in development. We are also developing mRNA expression profiles of glomerular podocytes lacking nephrin (mutated in congenital Finnish nephrotic syndrome) and LMX-1b (mutated in nail-patella syndrome). Our goal is to identify common pathways that lead to proteinuria.