MC1R失功能加重急性肾损伤的机制研究

急性肾损伤（AKI）因在住院患者中的高患病率、死亡率以及高花费成为全球瞩目的健康问题，但目前仍缺乏特异性的靶向治疗。巨噬细胞等免疫细胞介导的炎症反应，肾小管上皮细胞的直接损伤都是AKI发生的重要机制。黑皮质素可以通过系统性免疫调节作用、肾小管直接保护作用在AKI中发挥肾脏保护作用。然而，黑皮质素的肾脏保护作用究竟通过哪一种受体所介导目前尚未可知。鉴于巨噬细胞和肾小管上皮细胞均表达丰富的黑皮质素受体1(MC1R)，且在其他系统的研究和预实验结果显示MC1R的敲除或失功能将导致巨噬细胞的异常极化和相应脏器的损伤加重，因此，我们提出假设MC1R失功能将加重AKI肾脏损伤。为验证假设，我们应用先天性MC1R失功能小鼠制作AKI模型，从巨噬细胞和肾小管上皮细胞两方面探讨MC1R失功能对AKI的影响，同时通过骨髓移植制作骨髓嵌合体小鼠更深入的验证我们的假设。本研究将为AKI的新疗法提供理论依据。

Acute kidney injury (AKI) has become a global health challenge due to its high morbidity, mortality and high cost in hospitalized patients, but its therapeutic strategies is limited to non-specific symptomatic supportive treatment. The inflammation caused by immune cells, including macrophages and the cell death of renal tubular epithelial cells are involved in AKI. Melanocortin have a renoprotective effect in AKI mediated by systemic immunomodulation and directly protective effect on the renal tubular epitheliums. However, which receptor is responsible for the renoprotective effect of melanocortin is not known. Because of the abundant expression of melanocortin receptor 1 (MC1R) renal tubular epitheliums and macrophages, abnormal polarization in MC1R knockout cells, aggravated organ function in MC1R loss-of-function mouse, MC1R is considered to response the renoprotective effect of melanocortin. In order to verify the hypothesis, congenital MC1R loss-of-function mice will be used to induced the AKI model, primary epitheliums and macrophages isolated from the MC1R loss-of-function mice will be used to investigate the effect of MC1R loss-of-function to AKI. Moreve, MC1R loos-of-function chimeric mice will be constructed through bone marrow transplantation and used to validate our hypothesis profoundly. This study will provide new support for AKI therapeutic strategies.