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Abstract: FR-PO122

Apobec-1 Limits Cisplatin and Ischemia-Reperfusion-Induced AKI

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    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
  • Blanc, Valerie, Washington University in St Louis, St Louis, Missouri, United States
  • Davidson, Nicholas, Washington University in St Louis, St Louis, Missouri, United States
  • Moeckel, Gilbert W., 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

Cisplatin (CP) and Ischemia/reperfusion (I/R) Injury induces AKI whereby proximal tubules undergo regulated necrosis. Repair is almost complete after a single dose of CP. We now examine the role Apolipoprotein B MRNA Editing Enzyme Catalytic Subunit 1 (Apobec1) plays in the recovery from AKI.

Methods

Mice were given CP 15 mg/kg or subjected to 20 min IRI with contralateral nephrectomy and renal function, histology, mRNA, protein, lipids and single cell RNA sequencing were analyzed. Bone marrow-derived macrophages (BMDM) were isolated from WT and Apobec1 KO mice and treated with LPS and IL-4 that polarize BMDM to M1 and M2, respectively, followed by cytokine profiling.

Results

Apobec-1 KO caused more severe AKI, plasma creatinine (pCr) 2.07 mg/dL ± 0.59 (n=13) vs 0.23 mg/dL ± 0.09 (n=8) 3d, p < 0.01 and greater mortality than in WT. The kidneys of Apobec1 KO showed increased necrosis, neutrophil invasion, KIM-1, NGAL, RIPK3, MLKL, TLR2, TLR4, and ASCL4 levels compared to WT kidneys (p<0.01). I/R injury was greater in apobec1 KO as well (pCr 1.34 ± 0.22, n=6 vs 0.75 ± 0.06, n=5, p<0.05 than WT). Apobec1 expression was restricted to invading macrophages in WT animals and single cell RNA sequencing revealed markedly increased inflammatory cytokine expression in these invading macrophages in the apobec1 KO animals. BMDM from Apobec1 KO mice exhibited a maturation defect as they failed to polarize to M1 phenotype in response to LPS. The increase in macrophages seen in WT AKI kidneys was not observed in Apobec1 KO AKI kidney, suggesting a macrophage homing defect. The apobec1 KO animals showed enrichment of cytokine-cytokine receptor, NF-kappa B, chemokine, and TNF signaling pathways.

Conclusion

We have identified Apobec1 as a crucial gene regulating the necrotic response to IR- and CP-induced nephrotoxicity. The absence of Apobec1 in macrophages prevented the transition of a cell death promoting phenotype to one supporting repair and regeneration. Apobec1 is a critical pro-survival response to renal injury and increasing Apobec-1 activity could be an effective strategy to reduce or prevent AKI.