急性肾损伤（AKI）是以突发性肾功能下降为特征的临床综合征，目前机制未明且缺乏特异治疗。临床研究发现肾功能异常患者血胃泌素释放肽前体肽（ProGRP）升高，且与肾功能损伤呈正相关，但原因及其效应未明。预实验证实AKI患者及小鼠血ProGRP升高，并发现损伤肾小管中GRP及受体GRPR合成均增加，而抑制GRPR减轻肾损伤，提示异常激活的GRP/GRPR可能在AKI中扮演重要角色，机制尚未明确。我们进一步利用RNA-seq分析发现，转录因子STAT1可能是GRP/GRPR潜在的下游靶点，参与介导肾小管上皮细胞驱动的巨噬细胞浸润及后续炎症和损伤，此外STAT1可能正反馈地促进GRP合成，加重肾脏损害。因此，本课题拟采用GRPR敲除、肾小管特异性敲除和受体拮抗剂等手段，探明上皮细胞GRP/GRPR在AKI中激活的原因及其功能和潜在机制。这将有助于揭示AKI的深层发病机制，并为药物研发提供理论依据。

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid loss of renal function, but the underlying mechanism is not fully understood. Previous studies showed that ProGRP increased in the serum of patients with renal dysfunction, and the level was positively correlated with severity of renal injury, however, the mechanism and biological effect of GRP are still unknown. Our pilot study demonstrated that serum ProGRP level was increased in AKI patients and mice. We also detected increased production of GRP and GRPR receptor in injured renal tubules. Moreover, inhibition of GRPR alleviated renal injury, suggesting that over-activated GRP/GRPR may play an important role in AKI, and the mechanism remains to be determined. RNA-seq analysis revealed that transcription factor STAT1 may be a potential downstream target of GRP/GRPR signaling, and STAT1 may be involved in tubular epithelial cell-mediated macrophage infiltration, and then contribute to renal inflammation and injury. In addition, STAT1 may induce GRP synthesis by positive feedback loop, which needs to be verified. In this project, we intend to use GRPR knockout mice, kidney-specific conditional knockout mice and GRPR antagonists to explore the mechanism of GRP overproduction, the function and potential mechanisms of GRPR in AKI will be also determined. This project may provide a novel therapeutic target for the treatment of AKI.