急性肾损伤向慢性化转归（AKI-CKD）发生率高、预后不良，被认为与巨噬细胞密切相关。然而，直接干预肾脏巨噬细胞微环境，并不能完全逆转AKI-CKD的进展，是目前亟待解决的科学问题。我们发现，AKI慢性期最显著的特征是持续肾脏固有巨噬细胞（kidney-resident macrophage）浸润，同时存在精氨酸酶1（ARG-1）相关的代谢异常，这种异常与AKI-CKD的进展密切相关。据此，我们推测肾脏损伤微环境诱导固有巨噬细胞产生ARG-1消耗精氨酸，导致邻近细胞如肾小管上皮细胞、周细胞和纤维细胞精氨酸饥饿、功能障碍，并激活肌成纤维细胞，肾脏损伤迁延不愈。本研究拟利用可诱导性固有巨噬细胞ARG-1敲入/敲出小鼠，诱导AKI-CKD损伤模型，结合ARG-1靶向干预，明确肾脏固有巨噬细胞基于ARG-1的免疫代谢异常对AKI向慢性化和纤维化转归的影响和机制，为逆转AKI-CKD提供新的治疗思路

Patients who survive acute kidney injury (AKI) have a greater risk for chronic kidney disease (CKD). The true nature of AKI progressing to CKD is complex and poorly understood. It is identified that macrophage (Mø) plays a critical role in ischemia reperfusion injury (I/R) incited AKI that leads to fibrosis and chronic renal disease CKD. However, renal Mø are heterogeneous due to their phenotype plasticity in complex renal microenvironments. Therapeutic interventions targeting on Mø microenvironment showed no potential to halt the progression of CKD. Therefore, it needs to be a much greater understanding of the therapeutic targets of renal Mø to restore normal renal structure and function. Our recent studies have demonstrated that the significant feature of the chronic phase after AKI is the predominantly infiltration of kidney-resident macrophage with intrinsic arginase 1 (ARG-1) -related metabolic abnormalities. Accordingly, we speculate that renal damaged microenvironment induces intrinsic macrophages to produce ARG-1 and consume arginine, leading to arginine starvation and dysfunction in adjacent cells, accelerating chronic inflammation and progressive fibrosis. In this study, we will use the inducible intrinsic macrophage ARG-1 knock-in / knock-down mice to induce AKI-CKD injury model, or administration of ARG-1 inhibtor or siRNA, to explore wheather targeting on ARG-1 related immune metabolic abnormalities in kidney-resident macrophages can stop the progression of CKD.