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Abstract: PO0362

Defective Clearance of Nucleic Acids Exacerbates AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Venkatadri, Rajkumar, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Dogan, Murat, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Sabapathy, Vikram, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Mohammad, Saleh, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Sharma, Rahul, University of Virginia School of Medicine, Charlottesville, Virginia, United States
Background

Extracellular nuclear DNA and RNA released from dying cells can act as damage associated molecular pattern (DAMP) to trigger inflammatory pathology during acute kidney injury (AKI). Cell-free or cytoplasmic DNA can activate immune cells through the interferon stimulatory DNA (ISD) pathway to contribute to tissue damage. We aimed to understand immune dysregulation due to defective DNA clearance in the setting of murine AKI models. To study direct effect of defective DNA clearance in AKI, we utilized Three prime repair exonuclease (TREX1) deficient mice.

Methods

C57BL/6J (B6) mice or bone marrow derived macrophages (BMDM) were treated with poly I:C (pIC) to mimic elevated nucleic acid DAMPs. Bilateral ischemic reperfusion injury (IRI) or treatment of TREX1 deficient (TREX1 KO and TREX1 D18N) and STING KO mice with cisplatin (Csp), which causes DNA damage-induced AKI, was employed. Renal function was assayed using plasma creatinine (PCr) and blood urea nitrogen (BUN) levels. Levels of proinflammatory cytokines (IFNg, TNFa), renal injury markers (Kim1 and Ngal) and pro-inflammatory genes (Il1b, Mx1, Nos2, Ifi44, Tnfa and Il6) were measured by Flow cytometry, ELISA and RT-PCR. H&E-stained kidney sections were used to assess renal injury.

Results

Treatments of wildtype (WT) B6 mice with pIC upregulated proinflammatory cytokines leading to a Th1 predominance, indicative of excessive inflammatory predisposition. Csp and IRI induced significantly higher injury and dysfunction in TREX1 deficient (TREX1 KO and TREX1 D18N) mice. Kidney injury markers Kim1 and Ngal were also significantly elevated along with elevated proinflammatory cytokines. The TREX1 D18N mice subjected to IRI also exhibited upregulated recently activated (CD4+CD69hi) and elevated T effector memory (CD4+CD44+CD62Llo) phenotype confirming immune dysregulation. CD4 T cells in TREX1 D18N mice also had reduced levels of the anti-inflammatory cytokine IL-10. Interestingly, STING KO and TREX1 D18N-STING double KO mice also had exacerbated injury levels indicating the role of uncleared DNA and the cGAS-STING DNA sensor pathway in AKI as a result of TREX1 deficiency.

Conclusion

The study presents evidence of the role of TREX1 and uncleared DNA to cause immune dysregulation in AKI and supports employing approaches that can target DNA scavenging to counteract the burden of AKI.

Funding

  • NIDDK Support