Role of VEGF in Glomerular Endothelial Health & Diseases

VEGF 在肾小球内皮健康中的作用

• 批准号: 6822487
• 负责人: S. Ananth Karumanchi
• 金额: $ 35.15万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6822487
• 关键词: biological signal transduction; computer data analysis; electron microscopy; enzyme linked immunosorbent assay; glomerulonephritis; growth factor receptors; image processing; immunocytochemistry; in situ hybridization; inhibitor /antagonist; kidney disorder; kidney function; laboratory rat; nephrogenesis; neutralizing antibody; pathologic process; polymerase chain reaction; proteinuria; renal glomerulus; renal toxin; tissue /cell culture; vascular endothelial growth factors; western blottings

DESCRIPTION (provided by applicant): Glomerular endothelial damage plays an important role in the pathogenesis of several proteinuric renal disorders such as preeclampsia (PE), thrombotic microangiopathic purpuras (TTP), renal transplant rejection and various endocapillary glomerulonephritides. However, the mechanisms of endothelial damage and proteinuria in these disorders are poorly understood. It has been shown that vascular endothelial growth factor (VEGF) is not only an essential molecule for glomerulogenesis and kidney development, but also important for glomerular capillary repair in experimental models of glomerular disorders such as glomerulonephritides and TTP. VEGF is also abundantly expressed in the adult glomerulus during nondiseased states, but its role in glomerular health and disease is unclear. Recently, we have demonstrated that excess placental production of sFIt-1 (a circulating VEGF antagonist) in patients with PE is responsible for proteinuria, hypertension and. qlomerular endotheliosis, the classic pathologic lesion of PE. Moreover, massive proteinuria with glomerular endotheliosis has been recently described in glomerular podocyte-specific VEGF knockout mice. Additionally, VEGF signaling inhibitors usage in clinical cancer trials have resulted in proteinuria and hypertension in humans. Therefore, we hypothesize that VEGF and its receptors play an important role in not only maintaining glomerular endothelial health but also in maintaining normal glomerular integrity and the barrier to proteinuria. Disruption of VEGF signaling by antagonists may result in proteinuria in the short term and glomerulosclerosis in the long term. In this proposal, we will first characterize our sFIt-1 induced model of proteinuria and endotheliosis to understand the mechanisms of proteinuria in VEGF-deficient states. We will then elucidate the VEGF signaling pathways that mediate the barrier against proteinuria and maintain endothelial health using chimeric VEGF receptors in glomerular endothelial cell culture studies in vitro to be followed by definitive in vivo studies in rats using VEGF receptor agonists (such as placental growth factor that activates only Fit-1 and not FIk-l) and neutralizing antibodies against various VEGF receptors. We will then study the long-term renal and vascular consequences of VEGF blockade in rats specifically seeking the development of glomerulosclerosis and hypertension. Finally, we will study the effects of VEGF inhibitors and VEGF agonists in anti-Thyl.1 nephritis, a well-characterized experimental model of glomerulonephritis, in which capillary repair is thought to be important for the resolution of nephritis. Together, these studies will facilitate us to achieve our goal of understanding the role of VEGF and glomerular endothelial cell dysfunction in the pathogenesis of proteinuria and may lead to novel therapeutic options for glomerular endothelial diseases as well as clarify the renal toxicity profile of VEGF signaling inhibitors being developed for other diseases such as cancer.

描述（申请人提供）：肾小球内皮损伤在多种蛋白尿性肾脏疾病的发病机制中起着重要作用，例如先兆子痫（PE）、血栓性微血管病性紫癜（TTP）、肾移植排斥和各种毛细血管内肾小球肾炎。 然而，人们对这些疾病中内皮损伤和蛋白尿的机制知之甚少。 研究表明，血管内皮生长因子（VEGF）不仅是肾小球生成和肾脏发育的重要分子，而且在肾小球疾病（如肾小球肾炎和 TTP）实验模型中对肾小球毛细血管修复也很重要。 在非疾病状态下，VEGF 在成人肾小球中也大量表达，但其在肾小球健康和疾病中的作用尚不清楚。 最近，我们已经证明，PE 患者胎盘产生过多的 sFIt-1（一种循环 VEGF 拮抗剂）是导致蛋白尿、高血压等的原因。肾小球内皮增生症是PE的典型病理病变。 此外，最近在肾小球足细胞特异性 VEGF 敲除小鼠中描述了伴有肾小球内皮增生的大量蛋白尿。 此外，临床癌症试验中使用 VEGF 信号抑制剂已导致人类出现蛋白尿和高血压。因此，我们推测VEGF及其受体不仅在维持肾小球内皮健康方面发挥着重要作用，而且在维持正常肾小球完整性和蛋白尿屏障方面也发挥着重要作用。拮抗剂破坏 VEGF 信号传导可能会导致短期蛋白尿和长期肾小球硬化。在本提案中，我们将首先描述 sFIt-1 诱导的蛋白尿和内皮细胞增生模型，以了解 VEGF 缺乏状态下蛋白尿的机制。然后，我们将在体外肾小球内皮细胞培养研究中使用嵌合 VEGF 受体阐明介导蛋白尿屏障并维持内皮健康的 VEGF 信号传导途径，随后使用 VEGF 受体激动剂（例如仅激活 Fit-1 而不是 FIk-1 的胎盘生长因子）和针对各种 VEGF 受体的中和抗体在大鼠中进行明确的体内研究。 然后，我们将研究 VEGF 阻断对大鼠的长期肾脏和血管影响，特别是肾小球硬化和高血压的发展。 最后，我们将研究 VEGF 抑制剂和 VEGF 激动剂在抗 Thil.1 肾炎中的作用，Thyl.1 肾炎是一种特征明确的肾小球肾炎实验模型，其中毛细血管修复被认为对于肾炎的缓解很重要。总之，这些研究将有助于我们实现了解 VEGF 和肾小球内皮细胞功能障碍在蛋白尿发病机制中的作用的目标，并可能为肾小球内皮疾病提供新的治疗选择，并阐明正在开发的用于其他疾病（如癌症）的 VEGF 信号抑制剂的肾毒性特征。