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Abstract: FR-PO185

Kidney Mitochondrial DNA Contributes to Circulating IL-6 in Sepsis-Associated AKI

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Shen, Alice, University of California San Diego, La Jolla, California, United States
  • Kumar, Avnee Jaya, University of California San Diego, La Jolla, California, United States
  • Ix, Joachim H., University of California San Diego, La Jolla, California, United States
  • Singh, Prabhleen, University of California San Diego, La Jolla, California, United States
  • Hepokoski, Mark, University of California San Diego, La Jolla, California, United States
Background

Increased circulating cell-free mitochondrial DNA (CCF-mtDNA) and acute kidney injury (AKI) are associated with mortality in sepsis, but the role of CCF-mtDNA in the pathogenesis of sepsis-associated AKI (S-AKI) remains unclear. We hypothesized that CCF-mtDNA released from the injured kidney contributes to the systemic inflammatory response via IL-6 in S-AKI.

Methods

CCF-mtDNA isolated from the plasma of mice exposed to sepsis by cecal ligation and puncture (CLP) vs sham control (N=5-6/group) were sequenced and quantified by droplet digital PCR. Single nucleotide polymorphisms (SNPs) identified in the isolated mtDNA were compared to those found in the heart, kidney, liver, and lung of individual mice to infer tissue origin. In in-vitro studies, mouse bone marrow cells were treated with CpG (positive control), kidney mtDNA, or mitochondrial damage-associated molecular patterns (mtDAMPs) with and without DNase or toll-like receptor-9 inhibitor. IL-6 concentrations were compared across groups. In in-vivo studies, mice were injected with saline vs kidney mtDAMPs with and without DNase, and IL-6 concentrations were compared. Finally, CCF-mtDNA levels were quantified in the plasma of septic human subjects with and without AKI.

Results

CCF-mtDNA was significantly increased in the plasma of CLP mice compared to controls. Three out of five mice analyzed had unique SNPs in mtDNA fragments indicating kidney origin of release. In both in-vitro and in-vivo studies, exposure to kidney mtDAMPs led to increased IL-6 release, which was attenuated by treatment with TLR-9 inhibitor or DNase (Figure A). In human studies, plasma CCF-mtDNA levels were significantly increased in patients with S-AKI compared to those with sepsis without AKI, and increased CCF-mtDNA significantly correlated with plasma IL-6 (Figure B/C).

Conclusion

CCF-mtDNA released from the kidney contributes to increased plasma IL-6 in sepsis. Preserving kidney mitochondrial integrity, preventing mtDNA release, or clearing circulating mtDNA are translational avenues to pursue to decrease mortality from S-AKI.

Funding

  • NIDDK Support