Receptor-mediated actions of renin in kidney fibrosis

肾素在肾纤维化中的受体介导作用

• 批准号: 8106188
• 负责人: yufeng huang
• 金额: $ 13.43万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 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/8106188
• 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; Enzyme-Linked Immunosorbent Assay; 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; 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

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，肾素-血管紧张素系统(RAS)的激活和血管紧张素II(Ang II)的产生在纤维化肾脏疾病中起着除该系统血流动力学作用之外的关键作用。血管紧张素Ⅱ受体阻滞剂是过去二十年来治疗多种肾脏和心血管疾病的最大突破之一。然而，疾病的发展是缓慢的，但并没有停止。血管紧张素转换酶II阻滞剂的治疗局限性使其他分子不会阻碍疾病的进展。其中一个罪魁祸首和这笔赠款的对象是肾素，血管紧张素II的阻断显著提高了肾素的水平。具体的假设是，肾素除了将血管紧张素原转化为血管紧张素I外，还具有新的受体介导的作用，可能在肾脏纤维化中发挥作用。我们的假设基于以下观察：1)肾小球系膜细胞肾素受体的直接激活诱导成纤维细胞因子转化生长因子-β1和促纤维化蛋白的合成，2)肾素与该受体的结合激活丝裂原激活的蛋白激酶-1和2(ERK1和ERK2)，以及随后的信号转导导致转化生长因子-IJ的诱导。重要的是，这种受体介导的途径不依赖于肾素在Ang II生成中的作用。此外，血管紧张素Ⅱ受体阻滞剂引起的肾素升高与肾素受体在病变肾小球中共定位。长期目标是：1)了解受体介导的肾素作用在肾纤维化中的可能作用；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这一新信息：1)确定在体外观察到的肾素受体介导的促纤维化作用是否在实验性肾脏疾病模型中起作用。2)鉴定肾素结构表面特异性受体结合部位，探讨受体结合部位与其酶切位点的关系，为肾素受体介导的作用提供分子基础，了解肾素双重作用在纤维化疾病中的生物学作用。如果成功实施，我们的研究将提供一个重要的概念证明，肾素除了在Ang II的生成中发挥作用外，还具有新的受体介导的作用，Ang II在肾脏纤维化中发挥作用。肾素通过不同的结合部位具有双功能作用，这对于针对RAS在肾纤维化中的新治疗将是非常重要的。