Receptor-mediated actions of renin in kidney fibrosis

肾素在肾纤维化中的受体介导作用

基本信息

批准号：
7915708
负责人：
yufeng huang
金额：
$ 13.12万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7915708
关键词：
Active Sites Adrenal Glands Angiotensin II Angiotensin II Receptor Angiotensinogen Binding Binding Sites Biological Biological Assay Cardiovascular Diseases Cardiovascular system Cells Collagen Combined Modality Therapy Data Disease Disease Progression Disease model Dose Enalapril Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Fibronectins Fibrosis Generations Glomerulonephritis Goals Grant In Vitro Inactive Renin Kidney Kidney Diseases Left Ligands Liver Losartan Lung MAPK1 gene MAPK3 gene Mediating Mentors Methods Mitogen Activated Protein Kinase 1 Modeling Molecular Nanotechnology Nephritis Neuraxis Organ Pathway interactions Plasminogen Activator Platelet Factor 4 Play Proteins Rat-1 Rattus Receptor Gene Recombinants Regulation Renin Renin-Angiotensin System Research Role Severity of illness Signal Transduction Site Small Interfering RNA Specificity Staining method Stains Structural Biologist Structure Surface System TGFB1 gene Therapeutic Time Tissues Transforming Growth Factors anti-Thy-1 base cytokine design gene delivery system gene therapy hemodynamics in vivo in vivo Model mesangial cell nanoparticle nanovector neutralizing antibody novel novel therapeutics receptor receptor binding receptor expression targeted delivery three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): Activation of the renin-angiotensin system (RAS) and generation of angiotensin II (Ang II) have long been known to play a crucial role in fibrotic renal disease beyond the hemodynamic actions of this system. Ang II blockade has been one of the greatest therapeutic breakthroughs for a variety of renal and cardiovascular diseases in the past two decades. However, disease progression is slowed but not stopped. The therapeutic limitations of Ang II blockade leave other molecules unopposed to sustain disease progression. One of these culprits and the subject of this grant is renin, which is markedly elevated by Ang II blockade. The specific hypothesis is that renin, in addition to its role to convert angiotensinogen to Ang I, has novel receptor- mediated actions that could play a role in renal fibrosis. We base that hypothesis on the observations that 1) direct activation of the renin receptor in mesangial cells induces synthesis of the fibrogenic cytokine transforming growth factor (TGF)-B1 and profibrotic proteins, 2) Binding of renin to this receptor activates the mitogen-activated protein kinase-1 and -2 (ERK1 & ERK2) and subsequent signaling that leads to TGF-IJ induction. Importantly, this receptor-mediated pathway is independent of renin's role in Ang II generation. Moreover, the elevated renin induced by Ang II blockade is colocalized with the renin receptor in diseased glomeruli. The long-term goals are 1) to understand the possible role of receptor-mediated actions of renin in renal fibrosis and 2) to elucidate the molecular basis of these actions in disease. We propose to provide this new information by accomplishing the following Specific Aims: 1) To determine whether the receptor mediated profibrotic action of renin observed in vitro acts in vivo in experimental kidney disease models. 2) To identify the specific receptor-binding site on the surface of the renin structure and investigate the relationship between the receptor binding site and its enzymatic site in order to provide the molecular basis for the receptor-mediated actions of renin and understand the biological role of the dual effects of renin in fibrotic disease. Successfully carried out, our studies will provide an important proof-of concept that renin has novel receptor-mediated actions, in addition to its role in Ang II generation, which play a role in renal fibrosis. That renin has bifunctional actions via different binding sites will be of enormous importance to be considered for new treatments targeting RAS in renal fibrosis.

描述（由申请人提供）：长期以来，已知肾素 - 血管紧张素系统（RAS）的激活和血管紧张素II（ANG II）的产生在该系统的血液动力学作用之外，在纤维化肾脏疾病中起着至关重要的作用。在过去的二十年中，Ang II封锁一直是各种肾脏和心血管疾病的最大治疗突破之一。但是，疾病的进展速度减慢，但不会停止。 ANG II封锁的治疗局限性使其他分子没有反对以维持疾病的进展。这些罪魁祸首之一和这笔赠款的主题是肾素，它被Ang II封锁显着提升。具体假设是，除了将血管紧张素原转化为ANG I的作用外，肾素还具有新型受体介导的作用，可以在肾纤维化中发挥作用。我们以观察结果为基础，即1）肾小球细胞中肾素受体的直接激活诱导纤维化细胞因子转化生长因子（TGF）-B1和触发蛋白蛋白的合成，2）肾素与该受体的结合激活了该受体与米位激活蛋白激酶-1和-2和-2（ERK1＆-2（ERK1）激活TGF-JIJ感应。重要的是，该受体介导的途径与肾素在ANG II生成中的作用无关。此外，ANG II阻滞诱导的肾素升高与患病肾小球中的肾素受体共定位。长期目标是1）了解肾素在肾纤维化中的受体介导的作用的可能作用，以及2）阐明这些作用在疾病中的分子基础。我们建议通过实现以下特定目的来提供此新信息：1）确定在实验性肾脏疾病模型中，受体介导的肾素在体内观察到体内的纤维纤维化作用。 2）确定肾素结构表面上的特定受体结合位点，并研究受体结合位点及其酶位点之间的关系，以便为肾素的受体介导的作用提供分子基础，并了解肾素在纤维化疾病中的双重作用。我们的研究成功地进行了，将提供一个重要的概念，即肾素具有新型受体介导的作用，除了其在Ang II产生中的作用，这些作用在肾纤维化中发挥了作用。该肾素通过不同的结合位点具有双功能作用，对于针对肾纤维化中RA的新治疗方法将非常重要。