ENDOTHELIAL DYSFUNCTION, NITRIC OXIDE AND RENAL FAILURE

内皮功能障碍、一氧化氮和肾衰竭

基本信息

批准号：
7990202
负责人：
MICHAEL S GOLIGORSKY
金额：
$ 9.67万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-18 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7990202
关键词：
Angiostatins Apoptosis Area Arginine Blood Vessels Blood capillaries Cell physiology Cells Chronic Kidney Failure Cicatrix Detection Development Drops Endostatins Endothelial Cells Epithelial Epithelium Extracellular Matrix Fibrosis Functional disorder Glutathione Goals Hypoxia In Vitro Investigation Kidney Kidney Diseases Kidney Failure Legal patent Mediating Mediator of activation protein Mesenchymal Messenger RNA Microcirculation Modification Molecular Morphology Myofibroblast N,N-dimethylarginine Nephrosclerosis Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Oxidative Stress Perfusion Peroxides Phase Phenotype Physiology Play Prevention Process Production Property Protein Deficiency Proteins Proteomics Research Personnel Role SKIL gene Signal Pathway Smooth Muscle Superoxides Testing Therapeutic Time Tissues Transforming Growth Factor beta Tubular formation Video Microscopy capillary cell transformation glomerulosclerosis in vivo premature programs senescence tetrahydrobiopterin transdifferentiation vessel regression

项目摘要

DESCRIPTION (provided by applicant): Endothelial cell dysfunction (ECD), premature senescence and apoptosis are important contributors to capillary drop-out, glomeruosclerosis, tubulointerstitial scarring and progression of chronic renal disease. Previous studies showed decreased availability of nitric oxide (NO), decreased levels of tetrahydrobiopterin (BH4) and glutathione (GSH), oxidative stress, and accumulation of peroxides as leading causes of ECD. Elevated levels of asymmetric dimethylarginine (ADMA) further compound ECD by inhibiting NO synthease. Preliminary Studies showed induction of a profibrotic phenotype of endothelial cells subjected to elevated levels of ADMA. NOS inhibition resulted in the in vitro and in vivo manifestations of the loss of differentiated endothelial cell functions and acquisition of myofibroblast phenotype. The concept to be tested and further developed in this proposal ascribes to NO deficiency and ECD-induced endothelial-mesenchymal transdifferentiation the role of a trigger of 1) initial functional insufficiency of microcirculation followed by 2) structural phase of microvascular regression - prerequisites of tissue hypoxia and progressive nephrosclerosis. These goals will be accomplished through 1) elucidating profibrotic sequelae of NOS inhibition in vivo; 2) assessing the contribution of vascular non-perfusion and structural regression to glomerulosclerosis and tubulointerstitial scarring; 3) investigations into transdifferentiation of endothelial cells as a potentially important contributor to vascular drop-out; its stimulators and mediators, like TGF-beta, angiostatin and endostatin; 4) detection and identification of intracellular proteins deficient in nitrosothiol modification, as a cause of the downstream endothelial-mesenchymal transdifferentiation; and 5) attempts to ameliorate endothelial-mesenchymal transdifferentiation, vascular regression and nephrosclerosis using an intermediate in NO synthesis, hydroxy-L-arginine, which combines the properties of superoxide scavenger and NO donor. These studies will be performed using established approaches for studies into cell physiology, renal morphology, proteomics, and renal physiology, all available to the investigative team. It is anticipated that proposed set of studies should provide a broad view on the potentially important mechanism of vascular regression in chronic kidney disease - endothelial-mesencymal transdifferentiation, its contribution to nephrosclerosis and therapeutic actions of hydroxy-L-arginine, which can ameliorate NO deficiency, accompanied by endothelial-mesenchymal transdifferentiation and vascular drop-out, thus reducing progression of chronic renal diseases.

描述（由申请人提供）：内皮细胞功能障碍（ECD），过早衰老和凋亡是毛细血管辍学的重要因素，肾小球肌肉硬化，肾小管间质的疤痕和慢性肾脏疾病的进展。先前的研究表明，一氧化氮（NO）的可用性降低，四氢无生物蛋白酶（BH4）和谷胱甘肽（GSH）的水平降低，氧化应激以及过氧化物作为ECD的主要原因的积累。不对称二甲基精氨酸（ADMA）的水平升高，通过抑制无合酶进一步化合物ECD。初步研究表明，诱导了患ADMA水平升高的内皮细胞的纤维化表型。 NOS抑制作用导致了分化内皮细胞功能丧失和肌纤维细胞表型的获得的体外表现和体内表现。在本提案中要测试和进一步发展的概念归因于没有缺陷和ECD诱导的内皮间质跨分化的触发触发的作用1）微循环的初始功能不足，然后是2）微血管回归的结构相位 - 组织低氧和渐进式肾脏肾脏症的先决条件。这些目标将通过1）阐明体内NOS抑制后遗症实现； 2）评估血管非灌注和结构回归对肾小球硬化和肾小管间歇性疤痕的贡献； 3）研究内皮细胞转差的研究，这是血管辍学的潜在重要因素；它的刺激剂和介体，例如TGF-beta，angiostatin和endotototatin； 4）检测和鉴定缺乏硝基硫醇修饰的细胞内蛋白，这是下游内皮 - 间质转分化的原因； 5）试图使用无合成中的中间体（羟基-l-精氨酸中的中间体）改善内皮 - 间质转分化，血管消退和肾脏硬化，这结合了上氧化物可寻求者的特性和无供体。这些研究将使用既定的细胞生理学，肾脏形态，蛋白质组学和肾脏生理学的研究方法进行，所有这些研究都是可供调查团队使用的。可以预料，拟议的一组研究应提供有关慢性肾脏疾病中血管回归的潜在重要机制的广泛看法 - 内皮 - 及性质的转变，其对肾脏严重的贡献和对羟基 - l-精氨酸的治疗作用的贡献，可以通过羟基 - l-精氨酸的治疗作用，从而通过不良效应，伴随及其及其及其及其及其过于及以外的杂物液含量，以外外的杂物。减少慢性肾脏疾病的进展。