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:7317311
- 负责人:
- 金额:$ 34.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-12-01 至 2011-06-30
- 项目状态:已结题
- 来源:
- 关键词:8-Bromo Cyclic Adenosine MonophosphateANG geneAbbreviationsAccountingAcuteAddressAdenosineAdenosine-5&apos-(N-ethylcarboxamide)Adrenergic ReceptorAgonistAngiotensin ReceptorAngiotensinogenAngiotensinsAnimalsAntibodiesAppendixBindingBlood PressureBlood Urea NitrogenBlood flowBlood urea nitrogen measurementCREB1 geneCell DegranulationCell LineCell SeparationCell modelCellsChemotactic FactorsChemotaxisCholera ToxinChronicChronic Kidney FailureCollagenConditionCongenic MiceCreatinineCromoglicic AcidCultured CellsCyclic AMPCyclic AMP Response ElementCyclic AMP-Responsive DNA-Binding ProteinCytomegalovirusDataDexamethasoneDiabetic NephropathyDiseaseFibrosisFigs - dietaryFluorescenceForskolinFura-2Gene ExpressionGenesGlomerulonephritisHeartHistamineHistamine AgentsHomo sapiensHumanIL8 geneIndividualInfiltrationInflammationInjuryJuxtaglomerular ApparatusKidneyKidney DiseasesKidney TransplantationKnock-outKnockout MiceLinkLosartanMacula densaMagnetismMast Cell NeoplasmMast Cell StabilizerMeasuresMediator of activation proteinMembraneMessenger RNAModelingMolecularMonitorMusNephronsNerveNorepinephrineNumbersObstructionOrganPatientsPeptidyl-Dipeptidase APlasmaPlayPopulationPreparationProcessProductionProteinsProto-Oncogene Protein c-kitProtocols documentationPumpPurinergic P1 ReceptorsPyelonephritisRNA InterferenceRateRattusReceptor, Angiotensin, Type 1RecoveryRegulationRelative (related person)Renal functionReninRenin-Angiotensin SystemReportingReverse Transcriptase Polymerase Chain ReactionRodentRoleSequence HomologySilverSkin MastocytomaSmall Interfering RNASodium-Restricted DietSurfaceTechnologyTestingTimeTissuesTransfectionUreteral obstructionVascular resistanceangiogeninarteriolebasecell motilitycongenicdaydietary controlinterstitialkidney vascular structureloss of functionmRNA Expressionmast cellmigrationnovel therapeuticspreventreceptorresearch studyresponsesalt intaketherapeutic targetthioperamidevasoconstriction
项目摘要
DESCRIPTION (provided by applicant): 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.
描述(由申请人提供):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合计占需要肾移植的患者的 75% 以上。在这些情况下,慢性进行性肾纤维化伴随着功能性肾单位的丧失,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,但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。根据我们实验室最近报告的肥大细胞表达和释放活性肾素的证据,我们假设浸润肾脏的肥大细胞释放的肾素触发肾内 RAS 和局部血管紧张素 (ANG II) 的形成。该提案的总体目标是解决浸润性肥大细胞和肥大细胞肾素是否在缺血性器官损伤和纤维化中发挥重要作用的重要问题。使用进行性肾纤维化(单侧输尿管梗阻(DUO))模型,我们将研究肥大细胞肾素和局部 ANG II 产生在此过程中的作用,并研究腺苷在调节肥大细胞肾素基因表达中的作用。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 UUO 肾脏中的肥大细胞可预防肾纤维化。 4. 抑制肥大细胞释放的肾素可减少离体和灌注肾脏的血管收缩。 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中分离出的肥大细胞以及 HMC-1 细胞(人类肥大细胞的培养细胞模型)进行。 UUO 动物研究将在大鼠和肥大细胞缺陷的 c-Kit 敲除小鼠及其同类对照中进行。具体目标 II 将检查腺苷对肥大细胞肾素表达、合成和释放的调节。这些实验将使用分离的人肾肥大细胞和 HMC-1 细胞进行。如果我们的假设被证明是正确的,那么我们将确定一个新的治疗靶点(肥大细胞肾素),用于改善慢性肾脏病的肾功能。
项目成果
期刊论文数量(0)
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Randi Beth Silver其他文献
Randi Beth Silver的其他文献
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{{ truncateString('Randi Beth Silver', 18)}}的其他基金
Mast-Cell Renin and Local ANG II Formation
肥大细胞肾素和局部 ANG II 形成
- 批准号:
7903825 - 财政年份:2009
- 资助金额:
$ 34.14万 - 项目类别:
Mast-Cell Renin and Local ANG II Formation
肥大细胞肾素和局部 ANG II 形成
- 批准号:
7872788 - 财政年份:2002
- 资助金额:
$ 34.14万 - 项目类别:
Ionic Homeostasis in Hypovolemia: Renal Mechanisms
低血容量时的离子稳态:肾脏机制
- 批准号:
6551471 - 财政年份:2002
- 资助金额:
$ 34.14万 - 项目类别:
Ionic Homeostasis in Hypovolemia: Renal Mechanisms
低血容量时的离子稳态:肾脏机制
- 批准号:
6888944 - 财政年份:2002
- 资助金额:
$ 34.14万 - 项目类别:
Ionic Homeostasis in Hypovolemia: Renal Mechanisms
低血容量时的离子稳态:肾脏机制
- 批准号:
6755023 - 财政年份:2002
- 资助金额:
$ 34.14万 - 项目类别:
Mast-Cell Renin and Local ANG II Formation
肥大细胞肾素和局部 ANG II 形成
- 批准号:
7479750 - 财政年份:2002
- 资助金额:
$ 34.14万 - 项目类别:
Ionic Homeostasis in Hypovolemia: Renal Mechanisms
低血容量时的离子稳态:肾脏机制
- 批准号:
6640510 - 财政年份:2002
- 资助金额:
$ 34.14万 - 项目类别:
Mast-Cell Renin and Local ANG II Formation
肥大细胞肾素和局部 ANG II 形成
- 批准号:
7650190 - 财政年份:2002
- 资助金额:
$ 34.14万 - 项目类别:
Mast-Cell Renin and Local ANG II Formation
肥大细胞肾素和局部 ANG II 形成
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- 资助金额:
$ 34.14万 - 项目类别:
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