Mechanisms and therapeutic manipulation of retinoic acid signaling in Acute Kidney Injury

急性肾损伤(AKI)是一种严重的疾病，涉及肾功能在几个小时内迅速下降到 几天。严重的病例可能导致终末期肾脏疾病，有证据表明AKI是长期肾病的先兆 慢性肾病(CKD)。尽管如此，AKI还没有有针对性的临床治疗方法。具体地说，不存在任何治疗方法 可加速肾功能恢复或减轻损伤后的纤维化和慢性肾脏病。然而，肾脏 具有修复AKI后的固有能力，并有希望改善AKI介导的长期AKI 损伤在于开发新的治疗方法，可以增强组织修复的自然机制，从而减少 AKI后纤维化与慢性肾脏病的关系。巨噬细胞在协调AKI后的损伤和修复过程中发挥核心作用，但 AKI后巨噬细胞依赖修复的内在机制一直知之甚少。在最近的研究中 我们已经证明，维甲酸(RA)信号在调节这种巨噬细胞依赖的修复过程中起着重要作用 AKI后的纤维化和这一途径的治疗操作可能被用来安全地操作这种RA- 对AKI治疗益处的依赖反应。在这项提案中，我们计划进行一系列小鼠和细胞培养研究，以 探索RA信号调节这种反应的机制，并开发一种新的临床前治疗方法 平台，安全有效地增强肾脏局部RA信号通路的激活，以增加 巨噬细胞依赖的组织修复和减少AKI发作后发生长期CKD的可能性。

Acute kidney injury (AKI) is a serious disorder that involves a rapid decline in renal function over a period of hours to days. Severe cases can result in end-stage renal disease, and evidence suggests that AKI is a precursor to long-term chronic renal disease (CKD). Despite this, there is no targeted clinical treatment for AKI. Specifically, no therapies exist that accelerate renal recovery or decrease fibrosis and CKD when administered after injury. However, the kidney possesses an inherent capacity to repair after AKI, and a promising approach to ameliorate long-term AKI-mediated damage lies in developing novel therapies that can enhance the natural mechanisms of tissue repair in order to reduce fibrosis and CKD after AKI. Macrophages play a central role in coordinating the injury and repair process after AKI, but the intrinsic mechanisms control macrophage-dependent repair after AKI have been poorly understood. In recent studies we have shown that retinoic acid (RA) signaling plays an important role in regulating this macrophage-dependent repair and fibrosis after AKI and that therapeutic manipulation of this pathway might be used to safely manipulate this RA- dependent response for therapeutic benefit for AKI. In this proposal we plan a series of mouse and cell culture studies to explore the mechanisms by which RA signaling regulates this response, and to develop a novel pre-clinical therapeutic platform to safely and effectively enhance local activation of the RA signaling pathway in the kidney in order to increase macrophage-dependent tissue repair and reduce the likelihood of developing long-term CKD after an episode of AKI.