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

描述（由申请人提供）：大多数肾病进展到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。月牙状肾小球肾炎（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（Macrophages， MF）在GN的诱导和发展中起着重要作用，蛋白尿的大小和月牙形肾小球的百分比与巨噬细胞浸润肾小球的数量相关。巨噬细胞与导致终末期肾衰竭的不可逆疤痕有关。A2A腺苷受体（A2AR）是一种内源性炎症抑制剂，我们发现它在肾小球MF中表达。A2AR的激活可防止肾小球急性期的损伤。在已建立的GN的进展阶段，A2AR的激活（最迟在诱导抗GBM GN后的第14天）减少了进行性纤维化。A2AR激活可显著阻断MF对肾小球的浸润，抑制肾小球血栓反应蛋白-1 （ttp -1）和骨桥蛋白-1 （OPN-1）的表达。该提议的假设是MF A2AR激活通过抑制MF功能来阻止GN。为了验证我们的假设，我们计划：(1)确定MF A2AR激活在已建立的GN进展期肾脏保护中的贡献。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。(2)确定A2AR在MF上的激活如何预防进行性肾损伤的潜在机制。为了实现这一目标，我们将：(a)在A2AR缺陷小鼠和用A2AR缺陷和野生型MF重组并用A2AR激动剂治疗的MF缺失小鼠中鉴定TSP-1和OPN-1的表达；(b)确定A2AR激活是否调节TSP-1和/或OPN-1对进行性肾损伤的保护，通过过性转移TSP-1和OPN-1缺陷MF，并使用肾炎的TSP-1和OPN-1 KO小鼠加A2AR激动剂治疗。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后的纤维化提供一个概念性框架，这样它们可能被用作肾脏疾病和其他慢性炎症损伤的进行性纤维化的治疗靶点。

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.