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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（申请人提供）：内皮细胞功能障碍（ECD）、过早衰老和细胞凋亡是导致毛细血管脱落、肾小球硬化、小管间质瘢痕形成和慢性肾脏疾病进展的重要因素。先前的研究表明，一氧化氮（NO）可用性降低、四氢生物蝶呤（BH4）和谷胱甘肽（GSH）水平降低、氧化应激和过氧化物积累是ECD的主要原因。不对称二甲基精氨酸（ADMA）水平升高通过抑制NO合成酶进一步复合ECD。初步研究表明，ADMA水平升高可诱导内皮细胞的纤维化表型。NOS抑制导致体外和体内表现为分化内皮细胞功能丧失和肌成纤维细胞表型获得。这一概念有待进一步验证和发展，该建议将一氧化氮缺乏和ecd诱导的内皮-间充质转分化的作用归因于1)微循环初始功能不足，随后是2)微血管结构阶段退化——组织缺氧和进行性肾硬化的先决条件。这些目标将通过1)阐明NOS抑制在体内的纤维化后遗症；2)评估血管非灌注和结构退化对肾小球硬化和小管间质瘢痕形成的贡献；3)内皮细胞转分化作为血管脱落的潜在重要因素的研究；它的刺激剂和介质，如tgf -，血管抑制素和内皮抑制素；4)检测和鉴定细胞内亚硝基硫醇修饰缺陷蛋白，作为下游内皮-间充质转分化的原因；5)尝试利用一氧化氮合成中的一种中间体羟基- l-精氨酸来改善内皮-间质转分化、血管退化和肾硬化，它结合了超氧化物清除剂和一氧化氮供体的特性。这些研究将使用既定的方法进行研究，包括细胞生理学、肾脏形态学、蛋白质组学和肾脏生理学，所有这些都可供调查小组使用。我们期待这一系列的研究能为慢性肾脏疾病中血管退化的潜在重要机制——内皮-间质转分化、其对肾硬化的贡献以及羟基- l-精氨酸的治疗作用提供一个广阔的视角，羟- l-精氨酸可以改善一氧化氮缺乏，伴随内皮-间质转分化和血管退出，从而减少慢性肾脏疾病的进展。