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Kidney Week

Abstract: PO2620

BAM15 and Mitochondrial DNA Form a Drug-Companion Biomarker Pair Working Through Reactive Oxygen Species in Septic AKI

Session Information

Category: Acute Kidney Injury

  • 101 AKI: Epidemiology, Risk Factors, and Prevention

Authors

  • Tsuji, Naoko, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Tsuji, Takayuki, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Yamashita, Tetsushi, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Hu, Xuzhen, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Yuen, Peter S.T., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Star, Robert A., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Background

Sepsis is multifactorial, so drug-biomarker co-development is likely necessary for developing effective therapeutics. Administration of BAM15, a mitochondrial uncoupler, improved sepsis AKI mortality, kidney function, and mitochondrial function in kidney tubules (ASN, 2019). We now evaluate if BAM15 and mtDNA form a drug companion biomarker pair and are linked mechanistically.

Methods

Mice with sepsis AKI [cecum ligation/puncture (CLP) in CD-1 mice] were treated with BAM15 (5mg/kg IV) at 0h (early) or 6h (delayed) after surgery. Serial plasma and urinary mtDNA was measured by qPCR. This was mimicked in vitro by incubating mouse primary cultured proximal tubular cells (PTCs) with serum from CLP mice. Mitochondrial superoxide generation was measured by live cell imaging with MitoSox-Red. Mitophagy detected in Mt-Keima mice [transgenic for pH-sensitive ratiometric fluorescent protein] by measuring mitochondrial pH.

Results

Plasma and urinary mtDNA were increased in CLP mice starting at 3 hr after CLP. Delayed treatment with BAM15 (6 hr) decreased mtDNA at 12 hrs (Fig 1). CLP serum stimulated superoxide production and release of mtDNA into cultured PCT media; both were proportionately inhibited by BAM15 (Fig 2A-C). Released mtDNA correlated with superoxide production. BAM15 recovered mitochondrial biogenesis through activation of PGC1α pathway and, inhibited CLP reduction of mitophagy.

Conclusion

Sepsis increased kidney mtROS and released mtDNA from PT cells. BAM15 attenuated generation of mtROS and inhibited mtDNA release into urine and also circulating mtDNA even delayed BAM15 treatment. In sepsis AKI, BAM15 changed the trajectory of mitochondrial fate. Our results suggest that BAM15 and mtDNA are mechanistically linked via ROS, and form a drug-companion biomarker pair.

Funding

  • NIDDK Support