PDF(Pubmed)
Abstract：
Acute kidney injury (AKI) is a common clinical syndrome with complex pathogenesis, characterized by a rapid decline in kidney function in the short term. Worse still, the incomplete recovery from AKI increases the risk of progression to chronic kidney disease (CKD). However, the pathogenesis and underlying mechanism remain largely unknown. Macrophages play an important role during kidney injury and tissue repair, but its role in AKI-to-CKD transition remains elusive. Herein, single nucleus RNA sequencing (snRNA-Seq) and flow cytometry validations showed that E-type prostaglandin receptor 4 (EP4) was selectively activated in renal macrophages, rather than proximal tubules, in ischemia-reperfusion injury (IRI)-induced AKI-to-CKD transition mouse model. EP4 inhibition aggravated AKI-to-CKD transition, while EP4 activation impeded the progression of AKI to CKD though regulating macrophage polarization. Mechanistically, network pharmacological analysis and subsequent experimental verifications revealed that the activated EP4 inhibited macrophage polarization through inducing Carnitine palmitoyltransferase 2 (CPT2)-mediated lipophagy in macrophages. Further, CPT2 inhibition abrogated the protective effect of EP4 on AKI-to-CKD transition. Taken together, our findings demonstrate that EP4-CPT2 signaling-mediated lipophagy in macrophages plays a pivotal role in the transition of AKI to CKD and targeting EP4-CPT2 axis could serve as a promising therapeutic approach for retarding AKI and its progression to CKD.
摘要：
急性肾损伤(AKI)是临床常见的综合征,发病机制复杂。以短期内肾功能迅速下降为特征。更糟糕的是，AKI未完全恢复会增加进展为慢性肾脏病(CKD)的风险.然而,其发病机制和潜在机制尚不清楚。巨噬细胞在肾损伤和组织修复过程中发挥重要作用,但其在AKI到CKD转变中的作用仍然难以捉摸。在这里，单核RNA测序（snRNA-Seq）和流式细胞术验证显示E型前列腺素受体4（EP4）在肾巨噬细胞中被选择性激活，而不是近端小管，在缺血再灌注损伤（IRI）诱导的AKI到CKD转换小鼠模型中。EP4抑制加重了AKI到CKD的转变，而EP4激活通过调节巨噬细胞极化阻碍AKI向CKD的进展。机械上,网络药理学分析和随后的实验验证表明，激活的EP4通过诱导巨噬细胞中的肉碱棕榈酰转移酶2（CPT2）介导的脂质吞噬来抑制巨噬细胞极化。Further,CPT2抑制消除了EP4对AKI至CKD转换的保护作用。一起来看,我们的研究结果表明,巨噬细胞中EP4-CPT2信号介导的噬脂性在AKI向CKD的转变过程中发挥了关键作用,靶向EP4-CPT2轴可作为延缓AKI及其向CKD进展的有前景的治疗方法.
