Tissue Kallikrein, Oxidative Stress and Renal Fibrosis
Tissue Kallikrein, Oxidative Stress and Renal Fibrosis
批准号:
7084650
负责人:
JULIE CHAO
金额:
$28.23万
依托单位国家:
美国
项目类别:
财政年份:
2004
资助国家:
美国
项目状态:
已结题
起止时间:
2004-07-01 至 2008-06-30
关键词:
RNA interferenceangiotensin /renin /aldosterone hypertensionapoptosisbiological signal transductioncell morphologycell proliferationchronic renal failuredietary sodiumenzyme activityenzyme mechanismextracellular matrixfibrosisinflammationinterstitialkallikreinskidney functionkininslaboratory ratnephrosclerosisoxidative stresspathologic processsodium chloridetissue /cell culture
中文摘要
描述(由申请人提供):这项建议的目的是研究激肽释放酶系统(KKS)对盐诱导的肾硬化症的保护作用和信号机制。长期目标是在治疗和预防慢性肾脏疾病和终末期肾功能衰竭方面开发新的治疗靶点。在人类和患有肾脏疾病的动物模型中,肾脏激肽释放酶水平显著降低。通过连锁分析,我们发现人类组织激肽释放酶基因的启动子多态等位基因与盐诱导的高血压和终末期肾功能衰竭以及血压对饮食钠限制变化的反应有关。这些发现暗示KKS在盐敏感型高血压和肾功能中起重要作用。事实上,我们的初步研究表明,激肽释放酶/激肽释放酶水平升高(在激肽释放酶基因转移后)会抑制Dahl盐敏感(DS)大鼠盐诱导的炎症细胞浸润、肾小球增大、细胞凋亡、细胞增殖和胶原含量。这些保护作用伴随着一氧化氮(NO)水平的升高、氧化应激和转化生长因子-β表达的降低。基于这些发现,我们假设KKS通过形成NO,通过抑制氧化应激诱导的信号通路来预防和逆转盐诱导的肾硬化症。我们将从以下几个方面探讨KKS的信号转导机制:1)间质炎症,2)细胞凋亡,3)增殖和肥大,4)细胞外基质堆积导致纤维化。信号转导机制可能涉及MCP-1、VCAM-1、ICAM-1、核因子-kappaB、转化生长因子-β、MAPK、PA/MMPs、PI3-Kinase/Akt和p21/p27kip1。
通过将激肽释放酶基因和激肽释放酶蛋白注射到盐依赖型高血压大鼠模型中,激肽释放酶水平将得到提高。在培养的内皮细胞和肾细胞中,将使用特定的抑制物、中和抗体、显性-负性DNA结构和小干扰RNA来剖析细胞信号通路。这些研究应该提供关于激肽释放酶/激肽释放酶在预防和逆转导致盐诱导的肾硬化症的炎症、细胞凋亡、增殖、肥大和纤维化方面的作用的新的和深入的信息。
英文摘要
DESCRIPTION (provided by applicant): The objective of this proposal is to study the role and signaling mechanisms by which the kallikreinkinin system (KKS) protects against salt-induced nephrosclerosis. The long-term goal is to develop novel therapeutic targets in the treatment and prevention of chronic renal disease and end-stage renal failure. Renal kallikrein levels are markedly reduced in humans and animal models with renal disease. By linkage analysis, we showed an association of a promoter polymorphic allele in the human tissue kallikrein gene with salt-induced hypertension and end-stage renal failure, as well as with blood pressure responses to changes in dietary sodium restriction. These findings implicate an important role of the KKS in salt-sensitive hypertension and renal function. Indeed, our preliminary studies show that elevated kallikrein/kinin levels (following kallikrein gene transfer) results in suppression of salt-induced inflammatory cell infiltration, glomerular enlargement, apoptosis, cell proliferation and collagen content in Dahl salt-sensitive (DS) rats. These protective effects were accompanied by increased nitric oxide (NO) levels and reduced oxidative stress and TGF-beta expression. Based on these findings, we hypothesize that the KKS through NO formation prevents and reverses salt-induced nephrosclerosis through inhibition of oxidative stress-induced signaling pathways. The following Specific Aims will be pursued to determine the signaling mechanisms that mediate the protective effects of the KKS in: 1) interstitial inflammation, 2) apoptosis, 3) proliferation and hypertrophy and 4) extracellular matrix accumulation leading to fibrosis. The signaling mechanisms may involve MCP-1, VCAM-1, ICAM-1, NF-kappaB, TGF-beta, MAPK, PA/MMP, PI3-kinase/Akt and p21/p27kip1.
Enhanced kallikrein levels will be achieved by kallikrein gene delivery and kallikrein protein infusion into a salt-dependent hypertensive rat model. Cellular signaling pathways will be dissected in cultured endothelial and renal cells using specific inhibitors, neutralizing antibodies, dominant-negative DNA constructs, and small interference RNA. These studies should provide novel and in-depth information regarding the role of kallikrein/kinin in prevention and reversal of inflammation, apoptosis, proliferation, hypertrophy, and fibrosis that contribute to salt-induced nephrosclerosis.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Kallistatin in Vascular Injury
-
批准号:8974850
-
项目类别:
-
资助金额:$37.38万
-
财政年份:2013
-
负责人:JULIE CHAO
-
依托单位:
Kallistatin in Vascular Injury
-
批准号:8632049
-
项目类别:
-
资助金额:$37.38万
-
财政年份:2013
-
负责人:JULIE CHAO
-
依托单位:
Kallistatin in Vascular Injury
-
批准号:8788062
-
项目类别:
-
资助金额:$36.81万
-
财政年份:2013
-
负责人:JULIE CHAO
-
依托单位:
Regulation and Function of Tissue Kallikrein
-
批准号:7820918
-
项目类别:
-
资助金额:$5.14万
-
财政年份:2009
-
负责人:JULIE CHAO
-
依托单位:
SC COBRE: PROTEIN SCIENCE CORE
-
批准号:7610440
-
项目类别:
-
资助金额:$17.66万
-
财政年份:2007
-
负责人:JULIE CHAO
-
依托单位:
SC COBRE: PROTEIN SCIENCE CORE
-
批准号:7381845
-
项目类别:
-
资助金额:$20.53万
-
财政年份:2006
-
负责人:JULIE CHAO
-
依托单位:
SC COBRE: PROTEIN SCIENCE CORE
-
批准号:7171075
-
项目类别:
-
资助金额:$12.66万
-
财政年份:2005
-
负责人:JULIE CHAO
-
依托单位:
Tissue Kallikrein, Oxidative Stress and Renal Fibrosis
-
批准号:7249463
-
项目类别:
-
资助金额:$27.41万
-
财政年份:2004
-
负责人:JULIE CHAO
-
依托单位:
CORE--PROTEIN SCIENCE
-
批准号:6981758
-
项目类别:
-
资助金额:$9.16万
-
财政年份:2004
-
负责人:JULIE CHAO
-
依托单位:
Tissue Kallikrein, Oxidative Stress and Renal Fibrosis
-
批准号:6894827
-
项目类别:
-
资助金额:$28.91万
-
财政年份:2004
-
负责人:JULIE CHAO
-
依托单位:
Tissue Kallikrein, Oxidative Stress and Renal Fibrosis
-
批准号:6817573
-
项目类别:
-
资助金额:$28.91万
-
财政年份:2004
-
负责人:JULIE CHAO
-
依托单位:
BRADYKININ RECEPTORS IN HYPERTENSION
-
批准号:6184241
-
项目类别:
-
资助金额:$19.91万
-
财政年份:1997
-
负责人:JULIE CHAO
-
依托单位:
BRADYKININ RECEPTORS IN HYPERTENSION
-
批准号:6043821
-
项目类别:
-
资助金额:$19.34万
-
财政年份:1997
-
负责人:JULIE CHAO
-
依托单位:
BRADYKININ RECEPTORS IN HYPERTENSION
-
批准号:2409204
-
项目类别:
-
资助金额:$18.94万
-
财政年份:1997
-
负责人:JULIE CHAO
-
依托单位:
BRADYKININ RECEPTORS IN HYPERTENSION
-
批准号:2750412
-
项目类别:
-
资助金额:$18.68万
-
财政年份:1997
-
负责人:JULIE CHAO
-
依托单位:
KALLISTATIN IN HYPERTENSION
-
批准号:2901123
-
项目类别:
-
资助金额:$24.05万
-
财政年份:1990
-
负责人:JULIE CHAO
-
依托单位:
RENAL KALLIKREIN-BINDING PROTEIN IN HYPERTENSION
-
批准号:3362831
-
项目类别:
-
资助金额:$16.52万
-
财政年份:1990
-
负责人:JULIE CHAO
-
依托单位:
RENAL KALLIKREIN-BINDING PROTEIN IN HYPERTENSION
-
批准号:3362832
-
项目类别:
-
资助金额:$17.39万
-
财政年份:1990
-
负责人:JULIE CHAO
-
依托单位:
Kallistatin in Hypertension
-
批准号:6926772
-
项目类别:
-
资助金额:$29.2万
-
财政年份:1990
-
负责人:JULIE CHAO
-
依托单位:
KALLISTATIN IN HYPERTENSION
-
批准号:6389122
-
项目类别:
-
资助金额:$23.47万
-
财政年份:1990
-
负责人:JULIE CHAO
-
依托单位: