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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（由申请方提供）：内皮细胞功能障碍（ECD）、过早衰老和细胞凋亡是毛细血管脱落、肾小球硬化、肾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）的可用性降低，四氢生物蝶呤（BH 4）和谷胱甘肽（GSH）的水平降低，氧化应激和过氧化物的积累是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合成酶进一步化合物ECD。初步研究显示，ADMA水平升高可诱导内皮细胞的促纤维化表型。NOS抑制导致分化的内皮细胞功能丧失和肌成纤维细胞表型获得的体外和体内表现。在该提议中待测试和进一步发展的概念归因于NO缺乏和ECD诱导的内皮-间充质转分化的触发作用：1）微循环的初始功能不足，随后是2）微血管退化的结构阶段-组织缺氧和进行性肾硬化的先决条件。这些目标将通过以下方式实现：1）阐明体内NOS抑制的促纤维化后遗症; 2）评估血管无灌注和结构退化对肾小球硬化和肾小管间质瘢痕形成的贡献; 3）研究内皮细胞的转分化作为血管脱落的潜在重要贡献者;其刺激物和介质，如TGF-β、血管抑素和内皮抑素; 4）检测和鉴定作为下游内皮-间充质转分化的原因的亚硝基硫醇修饰缺陷的细胞内蛋白;和5）尝试使用NO合成中的中间体羟基-L-精氨酸来改善内皮-间充质转分化、血管退化和肾硬化，所述羟基-L-精氨酸结合了超氧化物清除剂和NO供体的性质。这些研究将使用研究团队可用的细胞生理学、肾脏形态学、蛋白质组学和肾脏生理学研究的既定方法进行。预计拟议的一组研究应提供对慢性肾脏疾病血管退化的潜在重要机制的广泛观点-内皮-间质转分化，其对肾硬化的贡献和羟基-L-精氨酸的治疗作用，其可以改善NO缺乏，伴随内皮-间质转分化和血管脱落，从而减少慢性肾脏疾病的进展。