Reduction of kidney progressive fibrosis by A2A adenosine receptor activation: P

通过 A2A 腺苷受体激活减少肾脏进行性纤维化：P

• 批准号: 8105831
• 负责人: GABRIELA E GARCIA
• 金额: $ 29.28万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105831
• 关键词: Acute; Adenosine A2A Receptor; Adoptive Transfer; Agonist; Angiogenesis Inhibitors; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Automobile Driving; Blood capillaries; Cells; Chronic; Cicatrix; Clinical Trials; Collagen; Crescentic Glomerulonephritis; Data; Deposition; Development; Disease; E-Cadherin; End stage renal failure; Fibrosis; Glomerular basement membrane antibody; Glomerulonephritis; Goals; Human; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Kidney; Kidney Diseases; Kidney Failure; Lead; Link; Morbidity - disease rate; Mus; Nephrology; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Proteinuria; Rattus; Renal glomerular disease; Role; Staging; Testing; Thrombospondin 1; Wild Type Mouse; adenosine receptor activation; capillary; clinically relevant; glomerular basement membrane; in vivo; inhibitor/antagonist; insight; macrophage; novel; osteopontin; outcome forecast; prevent; receptor; reconstitution; repaired; therapeutic target

DESCRIPTION (provided by applicant): Progression of most nephropathies to end-stage renal disease remains a major problem in nephrology. Thus, delaying the progression of kidney diseases or arresting its course is an essential management goal. Crescentic glomerulonephritis (GN) is a severe and rapidly progressive glomerular disease with a poor prognosis. Macrophages (MF) play an important role in the induction and development of GN and both the magnitude of proteinuria and the percentage of crescentic glomeruli are correlated with the number of MF that infiltrates the glomerulus. Macrophages are linked with the irreversible scarring that leads to end-stage kidney failure. A2A adenosine receptor (A2AR) is an endogenous inhibitor of inflammation that we have found is expressed in MF from nephritic glomeruli. Activation of A2AR prevents glomerular injury in the acute phase of GN. During the progressive phase of established GN, activation of A2AR (as late as day 14 after induction of anti GBM GN) reduces progressive fibrosis. A2AR activation significantly blocked MF infiltrating the glomeruli and suppressed the glomerular expression of thrombospondin-1 (TSP-1) and osteopontin-1 (OPN-1). The hypothesis of this proposal is that MF A2AR activation arrests GN via suppression of MF function. To test our hypothesis we plan to: (1) Determine the contribution of MF A2AR activation in kidney protection in the progressive phase of established GN. To accomplish this aim we will (a) selectively deplete MF during the established phase of anti-GBM GN and; (b) perform adoptive transfer of MF derived from A2AR deficient mice or wild type mice and treat them with A2AR agonist. (2) To identify potential mechanisms for how A2AR activation on MF acts to prevent progressive kidney damage. To accomplish this aim, we will: (a) identify expression of TSP-1 and OPN-1 in A2AR deficient mice and in mice depleted of MF and reconstituted with A2AR deficient and wild type MF and treated with A2AR agonist and; (b) determine if A2AR activation modulates TSP-1 and/or OPN-1 during protection from progressive kidney damage by adoptive transfer of TSP-1 and OPN-1 deficient MF and using nephritic TSP-1 and OPN-1 KO mice plus treatment with A2AR agonist. We believe our studies will provide a conceptual framework for understanding how A2A adenosine receptors effectively suppress chronic inflammation and consequent fibrosis such that they may be used as therapeutic target for progressive fibrosis in kidney disease and in other chronic inflammatory injuries in humans. PUBLIC HEALTH RELEVANCE: We believe that these studies have potential clinical relevance, since most forms of glomerulonephritis progress rapidly to ESRD. Current treatments are limited because blocking established inflammation is extremely difficult. We think that these studies will provide a conceptual framework for understanding how A2A adenosine receptors effectively suppress chronic inflammation and consequent fibrosis such that they may be used as therapeutic target for progressive fibrosis in kidney disease and in other chronic inflammatory injuries in humans.

描述（由申请人提供）：大多数肾病进展为终末期肾病仍然是肾脏病学的一个主要问题。因此，延缓肾脏疾病的进展或阻止其进程是一个重要的管理目标。新月体肾小球肾炎是一种严重的、进展迅速的肾小球疾病，预后差。巨噬细胞（MF）在肾小球肾炎的发生、发展过程中起重要作用，其浸润肾小球的数量与肾小球蛋白尿的量及新月体肾小球的比例有关。巨噬细胞与导致终末期肾衰竭的不可逆疤痕有关。A2 A腺苷受体（A2 A adenosine receptor，A2 AR）是一种内源性炎症抑制因子，在肾小球MF中表达。A2 AR的激活可防止GN急性期肾小球损伤。在已建立的GN的进行性阶段期间，A2 AR的激活（迟至抗GBM GN诱导后第14天）减少进行性纤维化。A2 AR激活显著阻断MF浸润肾小球，并抑制肾小球血小板反应蛋白-1（TSP-1）和骨桥蛋白-1（OPN-1）的表达。该提议的假设是MF A2 AR激活通过抑制MF功能来阻止GN。为了检验我们的假设，我们计划：（1）确定MF A2 AR激活在已建立的GN的进行性阶段中在肾保护中的贡献。为了实现这一目标，我们将（a）在抗GBM GN的建立阶段选择性地消耗MF，和（B）进行源自A2 AR缺陷型小鼠或野生型小鼠的MF的过继转移，并用A2 AR激动剂处理它们。(2)确定MF上A2 AR激活如何防止进行性肾损伤的潜在机制。（a）鉴定TSP-1和OPN-1在A2 AR缺陷型小鼠和MF耗尽并用A2 AR缺陷型和野生型MF重建并用A2 AR激动剂处理的小鼠中的表达;（B）确定在通过过继转移TSP-1和OPN-1来保护免于进行性肾损伤期间，A2 AR活化是否调节TSP-1和/或OPN-1。1缺陷型MF和使用肾炎TSP-1和OPN-1 KO小鼠加用A2 AR激动剂处理的小鼠的结果。我们相信我们的研究将为理解A2 A腺苷受体如何有效抑制慢性炎症和随之而来的纤维化提供概念框架，使得它们可以用作肾脏疾病和人类其他慢性炎性损伤中进行性纤维化的治疗靶点。 公共卫生关系：我们认为这些研究具有潜在的临床意义，因为大多数形式的肾小球肾炎进展迅速终末期肾病。目前的治疗方法是有限的，因为阻断已建立的炎症是非常困难的。我们认为这些研究将为理解A2 A腺苷受体如何有效抑制慢性炎症和随之而来的纤维化提供概念框架，使得它们可用作肾脏疾病和人类其他慢性炎症损伤中进行性纤维化的治疗靶点。