Role of VEGF in Glomerular Endothelial Health & Diseases

VEGF 在肾小球内皮健康中的作用

• 批准号: 7239601
• 负责人: S. Ananth Karumanchi
• 金额: $ 33.33万
• 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/7239601
• 关键词: Adult; Agonist; Angiogenic Factor; Antibodies; Biological Preservation; Blood capillaries; Clinical; Data; Development; Disease; Disruption; Edema; Endothelial Cells; Experimental Models; Filtration; Functional disorder; Glomerular Capillary; Glomerulonephritis; Goals; Graft Rejection; Healed; Health; Human; Hypertension; Immunohistochemistry; In Situ Hybridization; In Vitro; Incidence; Kidney; Kidney Diseases; Kidney Transplantation; Knockout Mice; Lead; Lesion; Letters; Longitudinal Studies; Malignant Neoplasms; Mediating; Membrane Proteins; Modeling; Nephritis; Nephrotic Syndrome; Pathogenesis; Pathologic; Patient currently pregnant; Patients; Personal Communication; Phase; Phenotype; Placenta; Placental Growth Factor; Play; Pre-Eclampsia; Pregnancy; Production; Proteinuria; Purpura; Range; Rattus; Recovery; Relative (related person); Resolution; Role; Signal Pathway; Signal Transduction; Testing; Thinking; Toxic effect; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Work; angiogenesis; capillary; glomerular basement membrane; glomerular endothelium; glomerular filtration; glomerulosclerosis; healing; in vivo; inhibitor/antagonist; insight; kidney vascular structure; nephrogenesis; neutralizing antibody; novel therapeutics; podocyte; programs; protein expression; receptor; repaired; slit diaphragm

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（由申请人提供）：肾小球内皮损害在几种蛋白尿肾脏疾病的发病机理中起着重要作用，例如前球比（PE），血栓性微血管疾病（TTP），肾脏移植剂抑制和各种内核副乳腺副乳腺癌。 但是，这些疾病中内皮损伤和蛋白尿的机制知之甚少。 已经表明，血管内皮生长因子（VEGF）不仅是肾小球发生和肾脏发育的必不可少的分子，而且对于肾小球疾病（如肾小球肾上腺素型和TTP）的实验模型中，对于肾小球毛细管修复也很重要。 在非统治状态下，在成人肾小球中也大量表达了VEGF，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患者中SFIT-1（循环VEGF拮抗剂）的胎盘产生过多，负责蛋白尿，高血压和。 Qlomerular内皮病，PE的经典病变病变。 此外，最近在肾小球足细胞特异性的VEGF敲除小鼠中描述了具有肾小球内皮病的大蛋白尿。 此外，在临床癌症试验中，VEGF信号传导抑制剂使用率导致人类蛋白尿和高血压。因此，我们假设VEGF及其受体在维持肾小球内皮健康方面起着重要作用，而且在维持正常的肾小球完整性和蛋白尿的障碍方面也起着重要作用。从长远来看，拮抗剂对VEGF信号的破坏可能会导致蛋白尿，并且长期肾小球硬化。在此提案中，我们将首先表征我们​​的SFIT-1诱导的蛋白尿模型和内皮病，以了解VEGF缺乏状态下蛋白尿的机制。然后，我们将阐明在肾小球内皮细胞培养研究中使用嵌合VEGF受体在体外使用嵌合VEGF受体介导屏障的VEGF信号通路，并在体外进行体外研究，然后在VEGF受体激动剂（例如，使用VEGF受体生长因子（如胎盘生长）进行活性抗体和非fik-fik-fik-lik-nitim and and and veribib）在体内进行确定的研究。 然后，我们将研究VEGF阻断的长期肾脏和血管后果，专门寻求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激动剂在抗硫代的作用。1肾炎是肾小球肾炎的特征良好的实验模型，其中毛细管修复被认为对分辨肾炎的分辨很重要。这些研究将共同​​实现我们的目标，以了解VEGF和肾小球内皮细胞功能障碍在蛋白尿发病机理中的作用，并可能导致新型的治疗方法，用于肾小球内皮疾病的肾小球内皮疾病，以及阐明VEGGF信号抑制剂的肾脏毒性以及其他针对其他疾病的肾脏毒性。

项目成果

Angiogenic factors in the pathogenesis of preeclampsia.

先兆子痫发病机制中的血管生成因素。

• DOI: 10.1016/s0070-2153(05)71009-7
• 发表时间: 2005
• 期刊: Current topics in developmental biology
• 作者: Yuan,Hai-Tao;Haig,David;AnanthKarumanchi,S
• 通讯作者: AnanthKarumanchi,S

Placental ischemia and soluble fms-like tyrosine kinase 1: Cause or consequence of preeclampsia?

• DOI: 10.1038/sj.ki.5002281
• 发表时间: 2007-05-01
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Karumanchi, S. A.;Epstein, F. H.
• 通讯作者: Epstein, F. H.

Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?

• DOI: 10.1016/j.ajog.2007.10.783
• 发表时间: 2008-04-01
• 期刊: AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
• 影响因子: 9.8
• 作者: Bdolah, Yuval;Lam, Chun;Karumanchi, S. Ananth
• 通讯作者: Karumanchi, S. Ananth