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Abstract: SA-PO082

TREM2 Macrophages Ameliorate the Transition of AKI-CKD via a PI3K/AKT Signaling Pathway

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Zhou, Yiming, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  • Zhang, Yating, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  • Luo, Siweier, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  • Du, Yufei, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  • Wang, Le, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  • Liang, Hanzhi, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Background

Macrophages have been shown to contribute to renal injury and fibrosis as well as repair. Their multiple phenotypes may explain the diverse functions of macrophages in acute kidney injury (AKI) and subsequent chronic kidney disease (CKD). TREM2 macrophages have recently been shown to play an important role in regulating tissue inflammation and repair. But their role in the AKI-CKD transition remains unclear.

Methods

A unilateral ischemia-reperfusion injury (UIRI) mouse model was used to generate the transition of AKI-CKD. After operation, sham and UIRI mice were sacrificed on day 14. Serum urine, and kidney samples of each mouse were collected. Serum creatinine and urea nitrogen levels were determined by ELISA. Urinal albumin levels were determined by a CBB gel staining method. qPCR and WB were used to determine the expression levels of genes and proteins in kidney samples. H&E, PAS, Masson and Sirus Red staining were used to evaluate the renal histology. Bone marrow-derived macrophages from WT and TREM2 knockout mice were harvested and treated with the hypoxia and reoxygenation (HR) condition. Stable TREM2 overexpression macrophages were used to investigate the renal protective effect in UIRI mice.

Results

In this study, we found that TREM2 macrophages play a strong protective role in the transition from AKI to CKD. The population of TREM2 macrophages was significantly increased in the UIRI-induced AKI-CKD transition mice. Knockout of Trem2 resulted in increased renal inflammation, exacerbated renal injury and fibrosis. In addition, we found that TREM2 expression enhanced macrophage phagocytosis but reduced the expression of pro-inflammatory cytokines, resulting in lower levels of tubular cell apoptosis and fibrosis. RNA-seq analysis revealed that these effects of TREM2 were controlled by PI3K/AKT pathway. Notably, the kidney injury and fibrosis in the UIRI mice was effectively attenuated by cell therapy with TREM2-overexpressing macrophages.

Conclusion

Our study demonstrates that TREM2 macrophages play a protective role in the transition of AKI-CKD and targeting TREM2 may be a therapeutic strategy for this disease.