VEGF Signaling in Endothelial and Glomerular Epithelial Cells in Preeclampsia

描述（由申请人提供）：子痫前期是一种妊娠特异性疾病，临床上以高血压和蛋白尿为特征，发生在妊娠20周后。这种情况的病因和发病机制仍然难以捉摸，导致未能制定具体的预防和治疗策略。最近的研究提供证据表明，子痫前期与血管内皮生长因子（VEGF）可溶性受体水平升高有关。这种可溶性受体，通常被称为sFlt-1（来自fms样酪氨酸激酶受体-1），可以结合并中和VEGF，从而降低妊娠期血管生成活跃所需的游离VEGF水平。我们假设低游离VEGF水平可能以双重方式促进子痫前期的发病机制：i)内皮功能障碍和ii)肾小球上皮细胞（足细胞）失调，分别导致子痫前期的两个主要临床表现：高血压和蛋白尿。我们已经证明，与正常妊娠相比，患有严重先兆子痫的妇女的肾脏部分的肾素（一种裂隙隔膜蛋白）下调。狭缝隔膜是一种特殊的细胞间连接，连接邻近的足细胞，代表肾脏中主要的、大小选择的过滤器。此外，我们已经证明，子痫前期的蛋白尿与尿中活足细胞的损失有关，即足细胞尿症。在Specific Aim 1中，我们将研究血浆sFlt-1水平升高、膈缝蛋白（包括nephrin）下调与足尿症之间的相关性，并探讨足尿症作为子痫前期可能的早期标志物的作用。我们推测足尿症可能发生在蛋白尿和子痫前期。

DESCRIPTION (provided by applicant): 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.