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Mast-Cell Renin and Local ANG II Formation

肥大细胞肾素和局部 ANG II 形成

基本信息

批准号：
7849380
负责人：
Randi Beth Silver
金额：
$ 6.76万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7849380
关键词：
8-Bromo Cyclic Adenosine Monophosphate ANG gene Abbreviations Accounting Acute Address Adenosine Adenosine-5&apos -(N-ethylcarboxamide)Adrenergic Receptor Agonist Angiotensin Receptor Angiotensinogen Angiotensins Animals Antibodies Binding Blood Pressure Blood flow CREB1 gene Cell Degranulation Cell Line Cell Separation Cell model Cells Chemotactic Factors Chemotaxis Cholera Toxin Chronic Chronic Kidney Failure Collagen Congenic Mice Creatinine Cromoglicic Acid Cultured Cells Cyclic AMP Cyclic AMP Response Element Cyclic AMP-Responsive DNA-Binding Protein Cytomegalovirus Data Dexamethasone Diabetic Nephropathy Disease Fibrosis Figs - dietary Fluorescence Forskolin Fura-2 Gene Expression Genes Glomerulonephritis Heart Histamine Histamine Agents Homo sapiens Human IL8 gene Individual Infiltration Inflammation Injury Juxtaglomerular Apparatus Kidney Kidney Diseases Kidney Transplantation Knock-out Knockout Mice Link Losartan Macula densa Magnetism Mast Cell Neoplasm Mast Cell Stabilizer Measures Mediator of activation protein Membrane Messenger RNA Modeling Molecular Monitor Mus Nephrons Nerve Norepinephrine Obstruction Organ Patients Peptidyl-Dipeptidase A Plasma Play Population Preparation Process Production Proteins Proto-Oncogene Protein c-kit Protocols documentation Pump Purinergic P1 Receptors Pyelonephritis RNA Interference Rattus Receptor, Angiotensin, Type 1 Recovery Regulation Relative (related person)Renal function Renin Renin-Angiotensin System Reporting Reverse Transcriptase Polymerase Chain Reaction Rodent Role Sequence Homology Silver Small Interfering RNA Sodium-Restricted Diet Surface Technology Testing Time Tissues Transfection Ureteral obstruction Vascular resistance arteriole base cell motility congenic dietary control interstitial kidney vascular structure loss of function mRNA Expression mast cell migration new therapeutic target prevent receptor research study response salt intake thioperamide vasoconstriction

项目摘要

Progressive kidney disease is characterized by the accumulation of fibrotic mediators in the kidney. Glomerulonephritis, diabetic nephropathy, pyelonephritis, and renovascular disease together account for over 75% of patients requiring renal transplants. In these conditions it is chronic progressive renal fibrosis with associated loss of functioning nephrons that results in irreversible renal injury. While the renin angiotensin system (RAS) has traditionally been viewed as a circulating axis, evidence is accumulating that an active intrarenal RAS plays an important role in chronic kidney disease and fibrosis. Based on recent evidence reported from our lab that mast cells express and release active renin, we hypothesize that renin released from mast cells infiltrating the kidney triggers intra-renal RAS and local angiotensin (ANG II) formation. The overall objective of this proposal is addressing the important issue of whether infiltrating mast cells and mast-cell renin, play a significant role in ischemic organ damage and fibrosis. Using a model of progressive renal fibrosis (unilateral ureteral obstruction (DUO)) we will study the role of mast cell renin and local ANG II production in this process as well as investigate the role of adenosine in regulating mast cell renin gene expression. Our preliminary results demonstrate: 1. Human and rodent kidney mast cells express active renin. 2. Mast cell deficient mice do not develop renal fibrosis with UUO 3. Stabilizing mast cells in rat UUO kidney prevents renal fibrosis. 4. Inhibiting the renin released from mast cells reduces vasoconstriction in isolated and perfused kidney. 5. Stimulating the adenosine A2b receptor increases mast cell renin gene expression. In Specific Aim I. we will characterize the molecular identity of mast cell renin and examine the effects of mast cell renin and local ANG II formation on fibrosis and vasoconstriction in UUO. These experiments will be done with mast cells isolated from human and rodent kidney and with HMC-1 cells, a cultured cell model of human mast cells. The UUO animal studies will be carried out in rat and mast cell- deficient c-Kit knockout mice and their congenic controls. Specific Aim II. will examine regulation of mast cell renin expression, synthesis, and release by adenosine. These experiments will be done with isolated human kidney mast cells and with HMC-1 cells. If our hypothesis is proven correct then we will have identified a novel therapeutic target (mast cell renin) for ameliorating renal function in chronic kidney disease.

进行性肾病的特征是肾脏中纤维化介质的积累。肾小球肾炎、糖尿病肾病、肾盂肾炎和肾血管疾病共同导致超过75%的患者需要肾移植。在这些情况下，这是慢性进行性肾纤维化伴随功能肾单位的丧失，导致不可逆的肾损伤。虽然肾素血管紧张素系统（RAS）传统上被视为循环轴，越来越多的证据表明活跃的肾内 RAS 在慢性肾脏疾病和纤维化中发挥着重要作用。根据最近我们实验室报告的证据表明肥大细胞表达并释放活性肾素，我们假设肾素浸润肾脏的肥大细胞释放的肥大细胞触发肾内 RAS 和局部血管紧张素 (ANG II) 形成。该提案的总体目标是解决是否渗透桅杆的重要问题细胞和肥大细胞肾素在缺血性器官损伤和纤维化中发挥重要作用。使用模型进行性肾纤维化（单侧输尿管梗阻（DUO））我们将研究肥大细胞肾素的作用和在此过程中局部 ANG II 的产生以及研究腺苷在调节肥大细胞中的作用肾素基因表达。我们的初步结果表明： 1. 人类和啮齿动物肾肥大细胞表达活性肾素。 2. 肥大细胞缺陷小鼠不会因 UUO 发生肾纤维化 3. 稳定大鼠肥大细胞 UUO 肾可预防肾纤维化。 4.抑制肥大细胞释放的肾素可减少血管收缩在分离和灌注的肾脏中。 5.刺激腺苷A2b受体增加肥大细胞肾素基因表达。在具体目标 I 中，我们将表征肥大细胞肾素的分子特性并检查肥大细胞肾素和局部 ANG II 形成对 UUO 纤维化和血管收缩的影响。这些实验将使用从人类和啮齿动物肾脏分离的肥大细胞以及 HMC-1 细胞（一种人类肥大细胞的培养细胞模型。 UUO 动物研究将在大鼠和肥大细胞中进行 c-Kit 缺陷型敲除小鼠及其同类对照。具体目标二。将检查肥大细胞的调节腺苷的肾素表达、合成和释放。这些实验将在孤立的人类身上进行肾肥大细胞和 HMC-1 细胞。如果我们的假设被证明是正确的，那么我们将确定一个用于改善慢性肾病肾功能的新治疗靶点（肥大细胞肾素）。