Abstract: FR-PO0165
Macrophages Derived from Renalase (RNLS) and Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 1 (Apobec1) Knockout Mice Fail to Rescue Cisplatin (CP)-Induced AKI
Session Information
- AKI: Mechanisms - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Guo, Xiaojia, Yale School of Medicine, New Haven, Connecticut, United States
- Xu, Leyuan, Yale School of Medicine, New Haven, Connecticut, United States
- Velazquez, Heino, Yale School of Medicine, New Haven, Connecticut, United States
- Chen, Tian-Min, Yale School of Medicine, New Haven, Connecticut, United States
- Safirstein, Robert L., Yale School of Medicine, New Haven, Connecticut, United States
- Desir, Gary V., Yale School of Medicine, New Haven, Connecticut, United States
Background
Previously we reported that RNLS and Apobec1 knockout are exquisitely sensitive to CP-AKI and CP-CKD. We identified that RNLS and Apobec1 are crucial to the outcome of the injury. We now explore the role of macrophages in that sensitivity.
Methods
Renal cells (RC) and Bone marrow-derived macrophages (BMDM) were isolated from either WT or KO mice for co-culture study. WT or KO BMDM were infused into KO mice treated with CP. Plasma BUN and Creatinine were measured at several time points following a 15mg/kg dose while single cell RNA sequencing, quantitative reverse transcription polymerase chain reaction (RTqPCR), immunohistochemistry, and immunoblotting were used to identify gene and protein expression differences.
Results
RNLS and Apobec1 showed profound effects on the course of AKI/CKD as RNLS KOs developed more severe CKD (plasma creatinine: 0.17±0.02 mg/dl for KO versus 0.11±0.01 mg/dl for WT, n=6, P<0.05) and none of the Apobec1 KOs survived the initial dose of CP. KO renal cells made less injury marker KIM-1 when co-cultured with WT BMDM than with KO BMDM. We then injected WT and KO BMDM to each KO mouse. WT macrophage infusion reduced kidney injury in Apobec1 KO (BUN 53.81±3.52 vs 72.74±1.4 mg/dL, n=4, p<0.01) and RNLS KO mice (49.16±4.39 vs 68.57±2.89 mg/dL, n=4, p<0.01) as compared to mice infused with KO BMDM and showed reduced KIM-1 and Ccl2 renal expression. Both KO BMDMs failed to polarize to M1 macrophage properly: RNLS KO BMDM overreact to lipopolysaccharide (LPS) and Apobec1 KO BMDM did not respond to LPS at all. BMDM from both RNLS KO and Apobec1 KO AKI showed more mitochondria damage than BMDM from WT AKI. These results suggest that M1 is necessary to eliminate dead cells to sustain survival.
Conclusion
Our results indicate that Apobec1 and RNLS are key cargo components within the macrophages and are crucial to the outcome of the injury and suggest that WT macrophages provide survival factors that attenuate renal injury to cisplatin. Infused WT macrophages can be a potent delivery system to protect CP-AKI.
Funding
- Other NIH Support