ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO0230

Apobec 1 Limits Cisplatin-Induced AKI by Regulating the Disposal of Pro-Ferroptotic Lipids

Session Information

  • AKI Mechanisms - 3
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Guo, Xiaojia, Yale University School of Medicine, New Haven, Connecticut, United States
  • Velazquez, Heino, Yale University School of Medicine, New Haven, Connecticut, United States
  • Chen, Tian-Min, Yale University School of Medicine, New Haven, Connecticut, United States
  • Blanc, Valerie, Washington University in Saint Louis, Saint Louis, Missouri, United States
  • Davidson, Nicholas, Washington University in Saint Louis, Saint Louis, Missouri, United States
  • Safirstein, Robert L., Yale University School of Medicine, New Haven, Connecticut, United States
  • Desir, Gary V., Yale University School of Medicine, New Haven, Connecticut, United States
Background

Cisplatin (CP) causes proximal tubules to undergo regulated necrosis. We previously reported that the RNA editing-specific cytosine deaminase Apobec1, which regulates mitochondrial metabolism, cell fate and proliferation pathways, plays a crucial role in recovery from this injury. Among the known RNA editing targets for APOBEC1 is the lipid transport protein Apob and as the resultant smaller APOB48 is the preferred secretory route of potentially cytotoxic triglycerides (TG), we now ask if absence of Apobec1 during CP-induced AKI, whose toxicity is accompanied by the accumulation of TGs and oxidant stress, worsens AKI.

Methods

Apobec1 knockout (ko) mice were given CP 15 mg/kg i.p. and renal function, histology, mRNA, protein and lipid content were analyzed and compared to wild type (WT) mice of similar genetic background. We overexpressed rat Apobec-1 in PT cells and assessed cell viability histologically and by WST-1 assay after CP exposure.

Results

Apobec-1 deletion resulted in more severe AKI, plasma creatinine 2.07 mg/dL ± 0.59 ( n=13) vs 0.23 mg/dL ± 0.09 (n=8) 3d, p < 0.01 in WT. Remarkably all Apobec1 ko mice died after 6 days, while WT animals all survived. Apobec1 KO kidneys showed greater necrosis and neutrophil counts. mRNA and protein levels of RIPK3, MLKL, TLR2, TLR4, and ASCL4 were markedly increased in Apobec-1 ko compared to WT kidneys (p<0.01). Overexpression of Apobec-1 in mouse PT reduced CP-induced cell death 2.35-fold versus cells transduced with vector alone (n = 4, p < 0.05). Overexpression of Apobec-1 increased the activities of kinases associated with survival (ERK, STAT3, and AKT) and inhibited those inducing cell death (IRF4, and JNK). Plasma tTG increased 2-fold higher in CP-treated Apobec1 ko mice compared to WT animals (104.3 ± 12.6 vs. 57.4 ± 9.1, n=4, p<0.05), while renal TG trended upward (437.1 ± 130.0 vs. 223.8 ± 121.5, n=4, p=0.27).

Conclusion

We have identified Apobec1 as a crucial gene regulating the necrotic response to CP-induced nephrotoxicity. Apobec1 limits lipid accumulation in the kidney following CP-induced AKI and limiting lipotoxicity. Increasing Apobec-1 activity could be an effective strategy to reduce or prevent CP-induced AKI.

Funding

  • NIDDK Support