RESOLUTION OF GLOMERULOSCLEROSIS

解决肾小球硬化症

• 批准号: 6696609
• 负责人: AGNES B. FOGO
• 金额: $ 30.58万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696609
• 关键词: angiotensin II; cell cycle; cell death; cell differentiation; cell proliferation; cyclin dependent kinase; cytokine; disease /disorder model; extracellular matrix; fibrinolysis; gene expression; genetically modified animals; glomerulosclerosis; growth factor; high performance liquid chromatography; in situ hybridization; inhibitor /antagonist; laboratory mouse; laboratory rat; male; metalloendopeptidases; nephrectomy; plasminogen activator inhibitors; polymerase chain reaction; renin angiotensin system; tissue /cell culture

Our previous work indicates that angiotensin induces expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of fibrinolysis and matrix degradation, in vitro and in vivo. A causal link between angiotensin and PAI-1 and sclerosis is supported by our in vivo demonstration that inhibition of angiotensin II (AII) selectively decreases expression of PAI-1, and that high doses of either a type 1 AII receptor antagonist, or angiotensin I converting enzyme inhibitor (ACEI) can even lead to resolution of existing, biopsy-proven sclerosis in the rat in the 5/6 nephrectomy model of progressive glomerulosclerosis. Based on these data, we hypothesize that inhibition of angiotensin II and PAI-1, by promoting matrix degradation and modulating cell growth/differentiation, is pivotal in resolution of sclerosis. The available mutant mice strains have so far not been utilized to examine mechanisms of progression of renal disease because of a lack of success in applying established models of progressive renal disease in the mouse. We now have in hand a model of progressive glomerulosclerosis in the mouse, which will be applied to the newly available mutant mice strains deficient for or overexpressing components of the plasmin/plasminogen activator system, that provide a unique opportunity to study mechanisms of resolution of sclerosis. We also have available a specific inhibitor of PAI-1, which will allow additional, time specific inhibition of PAI-1 and determination of its contribution to sclerosis and its reversal in vivo. We will use in vivo models together with in vitro experiments to examine the interactions of the renin angiotensin system and the plasmin/plasminogen activator system in sclerosis and its resolution.

我们之前的工作表明，血管紧张素在体外和体内诱导纤溶酶原激活剂抑制剂-1 (PAI-1) 的表达，PAI-1 是纤维蛋白溶解和基质降解的关键抑制剂。我们的体内证明支持血管紧张素和 PAI-1 与硬化之间的因果关系，即抑制血管紧张素 II (AII) 选择性降低 PAI-1 的表达，并且高剂量的 1 型 AII 受体拮抗剂或血管紧张素 I在进行性肾小球硬化症的 5/6 肾切除模型中，转换酶抑制剂 (ACEI) 甚至可以解决大鼠中现有的、经活检证实的硬化症。基于这些数据，我们假设通过促进基质降解和调节细胞生长/分化来抑制血管紧张素 II 和 PAI-1，对于解决硬化症至关重要。迄今为止，可用的突变小鼠品系尚未用于检查肾病进展机制，因为在小鼠中应用已建立的进行性肾病模型未取得成功。我们现在手头有一个进行性肾小球硬化的小鼠模型，该模型将应用于新近获得的缺乏或过度表达纤溶酶/纤溶酶原激活剂系统成分的突变小鼠品系，这为研究硬化的解决机制提供了独特的机会。我们还提供了一种 PAI-1 特异性抑制剂，它可以对 PAI-1 进行额外的、时间特异性的抑制，并确定其对硬化的贡献及其体内逆转。我们将使用体内模型和体外实验来检查肾素血管紧张素系统和纤溶酶/纤溶酶原激活剂系统在硬化及其解决中的相互作用。