Role of the downstream mediator of glucocorticoids, annexin A1, in the repair process of acute kidney injury

在急性肾损伤（AKI）中，内皮和上皮细胞损伤与局部肾血流动力学紊乱和促炎介质释放相关。作为对这些后一种介质的反应，白细胞迁移到肾实质中，并通过释放一氧化氮（NO）、超氧自由基（O2-）和胡萝卜素加重疾病，引起氧化/亚硝化应激和血管收缩，从而促进持续的组织缺氧和酸中毒。这些不良反应的内源性抑制剂包括消退素、保护素D1、脂氧素4和膜联蛋白超家族成员。这些抑制剂一起帮助解决炎症和恢复肾功能。糖皮质激素诱导蛋白膜联蛋白A1可能是一个关键组成部分，但其保护作用的机制仍有待阐明。我们推测，膜联蛋白A1，连同其受体，甲酰肽受体2（FPR2），形成肾内旁分泌系统，发挥肾保护作用的设置AKI，并可能有针对性的器官保护治疗策略。为了测试这一点，将在大鼠和膜联蛋白A1缺陷小鼠中诱导AKI。将选择炎症模型（大鼠中的抗Thy-1肾炎、小鼠中的抗GBM肾炎）和缺血方法（I/RI）。然后将以时间特异性和细胞特异性方式研究膜联蛋白A1和FPR 2的表达。将平行测定肾功能、血流动力学和形态学改变。在治疗方法中，我们将比较糖皮质激素与全长膜联蛋白A1和膜联蛋白A1 N-末端片段AC2 - 26在这些模型中的作用。为了阐明膜联蛋白A1保护作用的细胞机制，我们着手研究其在培养的肾细胞适应缺氧和酸中毒中的作用。总之，这些研究将促进我们对AKI恢复期和膜联蛋白A1的特殊作用的理解。最终，我们的目标是开发新的，基于机制的策略，以保护AKI期间的肾功能。

In acute kidney injury (AKI), endothelial and epithelial cell damage is interrelated with perturbed local renal hemodynamics and release of pro-inflammatory mediators. In response to these latter mediators, leukocytes migrate into the renal parenchyma and aggravate disease by the release of nitric oxide (NO), superoxide radicals (O2-), and prostaglandins causing oxidative/nitrosative stress and vasoconstriction and, thus, promote ongoing tissue hypoxia, and acidosis. Endogenous inhibitors of these adverse effects include resolvins, protectin D1, lipoxin 4, and members of the annexin protein superfamily. Together these inhibitors help resolve inflammation and restore renal function. The glucocorticoid-inducible protein annexin A1 may be a key component herein, but the mechanisms of its protective effects remain to be elucidated. We hypothesize that annexin A1, together with its receptor, the formyl peptide receptor 2 (FPR2), form an intrarenal paracrine system that exerts renoprotective effects in the setting of AKI, and may be targeted for organprotective therapeutic strategies. To test this, AKI will be induced in rats and annexin A1-deficient mice. Inflammatory models (anti Thy-1 nephritis in rats, anti GBM nephritis in mice) and an ischemic approach (I/RI) will be chosen. Expression of annexin A1 and FPR2 will then be studied in a time- and cell-specific manner. Renal function, hemodynamics, and morphological alterations will be determined in parallel. In a therapeutic approach we will compare the effects of glucocorticoids with those of full-length annexin A1 and the annexin A1 N-terminal fragment AC2- 26 in these models. To elucidate cellular mechanisms of protective annexin A1 effects, we set out to study its role in adaptation of cultured renal cells to hypoxia and acidosis. Taken together, these studies will advance our understanding of the recovery phase of AKI and the particular role of annexin A1. Ultimately we aim at developing novel, mechanism-based strategies for the preservation of renal function during AKI.