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: 8251206
• 负责人: GABRIELA E GARCIA
• 金额: $ 25.47万
• 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/8251206
• 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; public health relevance; 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）：大多数肾病的进展到终末期肾脏疾病仍然是肾脏科的主要问题。因此，延迟肾脏疾病的进展或逮捕其路线是一个基本的管理目标。新月肾小球肾炎（GN）是一种严重且快速进行的肾小球疾病，预后不良。巨噬细胞（MF）在GN的诱导和发育以及蛋白尿的大小和新月肾小球的百分比中起着重要作用。巨噬细胞与导致末期肾衰竭的不可逆疤痕有关。 A2a腺苷受体（A2AR）是一种炎症的内源性抑制剂，我们发现，在MF中，来自肾肾小球的MF表达。 A2AR的激活可防止GN急性相位的肾小球损伤。在已建立的GN的渐进阶段，A2AR的激活（直到抗GBM GN诱导后的第14天）会降低进行性纤维化。 A2AR激活显着阻断了肾小球渗透的MF，并抑制了血小板传播-1（TSP-1）和骨桥蛋白-1（OPN-1）的肾小球表达。该提议的假设是MF A2AR激活通过抑制MF功能会阻止GN。为了检验我们的假设，我们计划：（1）确定在已建立的GN的渐进阶段，MF A2AR激活在肾脏保护中的贡献。为了实现这一目标，我们将（a）在抗GBM GN的既定阶段有选择地耗尽MF； （b）对源自A2AR缺乏小鼠或野生型小鼠的MF进行继承转移，并用A2AR激动剂对其进行处理。 （2）确定A2AR激活MF的潜在机制，以防止肾脏损伤。为了实现这一目标，我们将：（a）确定在A2AR缺乏小鼠中的TSP-1和OPN-1的表达以及在MF耗尽的小鼠中，并用A2AR缺乏和野生型MF重构，并用A2AR激动剂治疗； （b）确定A2AR激活是否通过TSP-1和OPN-1缺陷MF的过继转移，并使用Nephritic TSP-1和OPN-1 KO小鼠加上A2AR激动剂治疗，可以通过TSP-1和OPN-1缺乏的MF来保护TSP-1和/或OPN-1。我们认为，我们的研究将提供一个概念框架，以了解A2A腺苷受体如何有效抑制慢性炎症和随之而来的纤维化，从而可以用作肾脏疾病和其他人类其他慢性炎症性损伤的治疗靶标。 公共卫生相关性：我们认为这些研究具有潜在的临床相关性，因为大多数形式的肾小球肾炎迅速发展到ESRD。目前的治疗是有限的，因为阻止已建立的炎症非常困难。我们认为，这些研究将提供一个概念框架，以了解A2A腺苷受体如何有效抑制慢性炎症和随之而来的纤维化，从而可以用作肾脏疾病和其他人类其他慢性炎症性损伤的治疗靶标。