TREM2 Receptor Restricts AKI to CKD Transition After Folic Acid Injury

Background: Acute kidney injury (AKI) is a serious clinical condition associated with high mortality, progression to chronic kidney disease (CKD), and systemic organ dysfunction. Understanding the underlying mechanisms regulating the AKI to CKD transition is critical for developing new therapies, as current interventions for CKD primarily focus on slowing disease progression and promoting lifestyle changes. Current studies indicate that macrophages play a critical role in the injury and repair process after AKI. During the initial post injury phase, pro-inflammatory macrophages promote tissue damage; however, during late stages, pro-reparative macrophages play a key role in mediating tubular repair. A detailed understanding of macrophage phenotypes at different stages in the injured kidney still requires further exploration. Methods: To investigate macrophage heterogeneity, we generated a comprehensive single-cell RNA (scRNA) sequencing atlas by integrating 17 publicly available datasets covering all stages (Day 1–28) post-AKI. Folic acid induced AKI was performed to Trem2WT and Trem2KO mice to test function of TREM2 receptor in AKI to CKD transition. Results: Using the comprehensive scRNA sequencing atlas, we identified a distinct macrophage cluster enriched after AKI, which we termed injury specific macrophages (ISMs). Trajectory inference suggest that ISMs are originated from infiltrated monocytes after AKI. Over time, ISMs exhibited gene expression signatures characteristic of lipid-associated macrophages (LAMs), including Trem2. Temporal analysis also revealed that Trem2 expression in ISMs is correlated with a reduction in pro-inflammatory genes and an induction of pro-reparative genes. Cell-cell communication analysis predicted that ISMs interact with tubular epithelial cells through pro-reparative cytokines, suggesting a role in promoting tissue repair. Indeed, folic acid (FA) induced AKI resulted in worsened fibrosis and kidney function in Trem2-/- mice compared to Trem2WT mice. Conclusion: These data suggest that the TREM2 receptor on ISMs plays a protective role in the AKI-to-CKD transition. Deciphering the role of TREM2 in kidney injury may lead to novel macrophage-targeted therapeutic strategies to enhance tissue repair in patients with AKI.