Resolution of Glomerulosclerosis

肾小球硬化症的解决

• 批准号: 7791440
• 负责人: AGNES B. FOGO
• 金额: $ 29.64万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791440
• 关键词: Angiogenic Factor; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Angiotensin II Type 1 Receptor Blockers; Angiotensins; Antihypertensive Agents; Area; Blood Pressure; Blood Vessels; Blood capillaries; Cell Communication; Cell Line; Cells; Chronic Kidney Failure; Cicatrix; Dialysis procedure; Dose; End stage renal failure; Endothelial Cells; Extracellular Matrix; Extracellular Matrix Degradation; Fibrin; Fibrosis; Funding; Genetic; Glomerular Capillary; Growth; Growth Factor; Hormones; Hypertension; In Vitro; Injury; Intervention; Kidney Failure; Link; Mediating; Modeling; Mus; Nephrectomy; Plasminogen Activator Inhibitor 1; Process; Rattus; Regulation; Renin-Angiotensin System; Renin-Angiotensin-Aldosterone System; Resolution; Role; Sclerosis; Testing; Time; Transgenic Mice; Transplantation; Vascular Endothelial Growth Factors; Work; base; capillary; cell motility; factor A; genetic manipulation; glomerulosclerosis; in vivo Model; injured; kidney vascular structure; novel; overexpression; podocyte; receptor; research study; response

DESCRIPTION (provided by applicant): 1) Project summary: Our previous work indicates that regression of glomerulosclerosis can be achieved by high dose angiotensin inhibition. We have established that the type 1 receptor antagonist (AT1 RA) not only decreases extracellular matrix (ECM) synthesis, but is also linked to enhanced ECM degradation by decreasing expression of plasminogen activator inhibitor-1 (PAI-1), which promotes fibrin/matrix degradation and modulates cell migration and growth. Decreased PAI-1 induced by AT1RA is tightly linked to regression of sclerosis. Based on these findings, we now hypothesize that regression of existing sclerosis is mediated via coordination of 2 pivotal processes: resorption of existing areas of scar and new capillary growth. We further hypothesize that AT1 RA promotes regression by decreasing ECM accumulation, as well as by promoting glomerular capillary growth driven by key angiogenic factors, vascular endothelial-derived growth factor (VEGF)-A and the angiopoietins 1 and 2. VEGF-A and angiopoietin-1 (Ang1) are normally derived from the podocyte. We will examine mechanisms of capillary growth by genetic manipulations with systemic and/or podocyte-specific overexpression of VEGF-A and Ang1 and also Ang2, and inhibition of the renin aldosterone angiotensin system (RAAS). Inducible podocyte-specific transgenic mice will allow determination of the impact of these capillary growth mechanisms in regression. We have established primary podocyte cultures from wildtype and genetically manipulated mice, and obtained a glomerular endothelial cell (GEN) line, which will allow us to explore effects of podocyte injury and AT1RA on capillary growth and ECM regulation. We will use these novel in vivo models together with in vitro experiments to examine the interactions of the RAAS, PAI-1, ECM modulation and capillary growth to determine mechanisms of regression of glomerulosclerosis. 2) Relevance: Inexorable scarring of the kidney's vascular filtering units, the glomeruli, is a major cause of kidney failure, necessitating dialysis or transplant. Reversal of this process can be accomplished by inhibiting angiotensin, a key hormone that promotes hypertension and scarring. We will investigate how we can achieve breakdown of scar tissue and growth of new cells in concert to reverse scarring, and have more open, less scarred glomeruli that can filter better.

描述（由申请人提供）：1）项目摘要：我们以前的工作表明，高剂量血管紧张素抑制可以实现肾小球硬化的消退。我们已经确定，1型受体拮抗剂（AT1 RA）不仅降低了细胞外基质（ECM）合成，而且还通过降低质激素原激活剂抑制剂-1（PAI-1）的表达而与ECM降解相关，从而促进纤维蛋白//纤维蛋白//基质降解并调节细胞迁移和生长。 AT1RA诱导的PAI-1降低与硬化症的消退密切相关。基于这些发现，我们现在假设现有硬化症的回归是通过2个关键过程的协调来介导的：疤痕和新毛细血管生长的现有区域的吸收。我们进一步假设，AT1 RA通过减少ECM积累以及促进由关键血管生成因子，血管内皮衍生的生长因子（VEGF）-A和Angiopoietins驱动的肾小球毛细血管生长来促进回归。 -1（ANG1）通常源自足细胞。我们将通过遗传操作进行毛细管生长的机制，该机制通过遗传操作，具有全身性和/或足细胞特异性过表达的VEGF-A和ANG1以及ANG2，以及抑制肾素醛固酮血管紧张素系统（RAAS）。可诱导的足细胞特异性转基因小鼠将允许确定这些毛细血管生长机制在回归中的影响。我们已经从野生型和遗传操纵小鼠建立了原发性足细胞培养物，并获得了肾小球内皮细胞（Gen）系，这将使我们能够探索足细胞损伤和AT1RA对毛细血管生长和ECM调节的影响。我们将使用这些新型的体内模型以及体外实验来检查RAAS，PAI-1，ECM调节和毛细血管生长的相互作用，以确定肾小球硬化回归的机制。 2）相关性：肾脏血管过滤单元的不可分割的疤痕，肾小球是肾衰竭的主要原因，需要透析或移植。可以通过抑制血管紧张素来实现此过程的逆转，这是一种促进高血压和疤痕的关键激素。我们将调查如何在协调一致的疤痕组织中实现疤痕组织的分解和新细胞的生长，以逆转疤痕，并具有更开放的，更不疤痕的肾小球，可以更好地过滤。