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: 8440817
• 负责人: GABRIELA E GARCIA
• 金额: $ 24.58万
• 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/8440817
• 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.

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基本的管理目标。新月体肾炎(GN)是一种严重且进展迅速的肾小球疾病，预后不良。巨噬细胞在肾小球肾炎的发生发展中起着重要作用，蛋白尿的大小和新月体肾小球的百分率与巨噬细胞渗入肾小球的数量密切相关。巨噬细胞与导致终末期肾功能衰竭的不可逆转的疤痕有关。A2A腺苷受体(A2AR)是一种内源性炎症抑制因子，我们已发现在肾炎肾小球的MF中有表达。A2AR的激活可预防GN急性期的肾小球损伤。在已建立的肾小球肾炎的进展期，A2AR的激活(直到诱导抗GBM GN后的第14天)可减少进行性纤维化。A2AR的激活可明显阻断MF向肾小球的渗透，并抑制肾小球TSP-1和OPN-1的表达。这一假设认为，MFA2AR的激活通过抑制MFA2AR的功能来抑制GN。为了验证我们的假设，我们计划：(1)确定肾小球肾炎进展期MFA2AR激活在肾脏保护中的作用。为了达到这一目的，我们将(A)在建立的抗GBM GN阶段选择性地消耗MF；(B)过继转移来自A2AR缺陷小鼠或野生型小鼠的MF，并用A2AR激动剂治疗它们。(2)明确A2AR在MF上的激活如何起作用以防止进行性肾损害的潜在机制。为了实现这一目标，我们将：(A)确定TSP-1和OPN-1在A2AR缺陷小鼠和缺乏MF的小鼠中的表达，并用A2AR激动剂治疗重组A2AR缺陷和野生型MF；以及(B)通过过继转移TSP-1和OPN-1缺陷MF以及使用肾炎性TSP-1和OPN-1 KO小鼠加上A2AR激动剂治疗，确定A2AR激活是否调节TSP-1和/或OPN-1。我们相信，我们的研究将为理解A2A腺苷受体如何有效抑制慢性炎症和随之而来的纤维化提供一个概念性框架，以便它们可以被用作肾脏疾病和其他慢性炎症性损伤的进行性纤维化的治疗靶点。