Acute kidney injury (AKI) to chronic kidney disease (CKD) progression has become a life-threatening disease. However, an effective therapeutic strategy is still needed. The pathophysiology of AKI-to-CKD progression involves chronic inflammation and renal fibrosis driven by macrophage activation, which is physiologically dependent on colony-stimulating factor-1 receptor (CSF-1R) signaling. In this study, we modulated macrophage infiltration through oral administration of the CSF-1R inhibitor GW2580 in an ischemia–reperfusion (I/R)-induced AKI model to evaluate its therapeutic effects on preventing the progression of AKI to CKD. We found that GW2580 induced a significant reduction in the number of macrophages in I/R-injured kidneys and attenuated I/R-induced renal injury and subsequent interstitial fibrosis. By flow cytometry, we observed that the reduced macrophages were primarily Ly6C⁺ inflammatory macrophages in the GW2580-treated kidneys, while there was no significant difference in the number and percentage of Ly6C⁻CX3CR1⁺ macrophages. We further found that these reduced macrophages also demonstrated some characteristics of M2-like macrophages, which have been generally regarded as profibrotic subtypes in chronic inflammation. These results indicate the existence of phenotypic and functional crossover between Ly6C⁺ and M2-like macrophages in I/R kidneys, which induces AKI worsening to CKD. In conclusion, therapeutic GW2580 treatment alleviates acute renal injury and subsequent fibrosis by reducing Ly6C⁺ M2-like macrophage infiltration in ischemia-induced AKI.

急性肾脏损伤（AKI）演变为慢性肾脏疾病（CKD）已成为威胁生命的疾病。但是，仍然需要有效的治疗策略。AKI到CKD进展的病理生理学涉及由巨噬细胞激活驱动的慢性炎症和肾纤维化，其在生理上依赖于集落刺激因子1受体（CSF-1R）信号传导。在这项研究中，我们通过在缺血再灌注（I / R）诱导的AKI模型中口服CSF-1R抑制剂GW2580来调节巨噬细胞浸润，以评估其预防AKI向CKD进展的治疗效果。我们发现GW2580导致I / R损伤的肾脏巨噬细胞数量显着减少，I / R诱导的肾损伤和随后的间质纤维化减弱。通过流式细胞仪GW2580治疗的肾脏中的⁺炎性巨噬细胞，而Ly6C ^- CX3CR1 ⁺巨噬细胞的数量和百分比没有显着差异。我们进一步发现这些减少的巨噬细胞还表现出M2样巨噬细胞的某些特征，这些特征通常被认为是慢性炎症中的纤维化亚型。这些结果表明I / R肾脏中Ly6C ⁺和M2样巨噬细胞之间存在表型和功能交叉，这会导致AKI恶化为CKD。总之，GW2580的治疗方法是通过减少缺血诱导的AKI中的Ly6C ⁺ M2样巨噬细胞浸润减轻急性肾损伤和随后的纤维化。