VEGF Signaling in Endothelial and Glomerular Epithelial Cells in Preeclampsia

描述（由申请人提供）：先兆子痫是一种妊娠特异性疾病，临床特征为妊娠20周后发生的高血压和蛋白尿。这种疾病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。最近的研究提供了证据表明，先兆子痫与血管内皮生长因子（VEGF）的可溶性受体水平升高有关。这种可溶性受体，通常称为sFlt-1（来自fms样酪氨酸激酶受体-1），可以结合并中和VEGF，从而降低妊娠期活跃血管生成所需的游离VEGF水平。我们推测，低游离VEGF水平可能通过引起：i）内皮功能障碍和ii）肾小球上皮细胞（足细胞）失调以双重方式促成先兆子痫的发病机制，分别导致先兆子痫的两个主要临床表现，高血压和蛋白尿。我们已经证明，nephrin，一种裂隔膜蛋白，在患有重度先兆子痫的妇女的肾脏切片中与正常妊娠相比下调。狭缝隔膜是一种专门的细胞与细胞的连接，连接相邻的足细胞，代表肾脏中主要的大小选择性过滤器。此外，我们已经证明先兆子痫中的蛋白尿与尿中存活足细胞的丢失有关，即，足细胞尿症在具体目标1中，我们将研究血浆sFlt-1水平升高、裂膈蛋白（包括nephrin）下调和足细胞尿之间的相关性，并探讨足细胞尿作为先兆子痫早期标志物的作用。我们推测足细胞尿可能发生在蛋白尿和先兆子痫之前。 我们还推测，内皮功能障碍，先兆子痫的标志，导致高血压，是介导的部分低游离VEGF水平，可能会导致内皮一氧化氮合酶活性和一氧化氮的生产减少。这一假设将在具体目标2中进行检验。在具体目标3中，我们将研究缺陷的VEGF信号转导可能下调nephrin，破坏裂隔膜，导致足细胞尿，最终导致先兆子痫中的蛋白尿的机制。这些研究将为子痫前期的病理生理学基础的基本机制提供见解，这对于开发更具体的诊断和治疗方法至关重要。 相关性：先兆子痫影响美国5%的妊娠，仍然是孕产妇和胎儿发病率和死亡率的主要原因之一。目前，唯一的治疗方法是分娩，这往往导致早产和新生儿高发病率。更有效的治疗策略的发展，关键取决于更好地了解潜在的致病机制。

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.