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Kidney Week

Abstract: FR-PO111

BAM15, A New Mitochondrial Uncoupler, Improves Sepsis AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

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

Group or Team Name

  • Renal Diagnostics and Therapeutics Unit, NIDDK, NIH
Background

(2-fluorophenyl){6-[(2-fluorophenyl)amino](1,2,5-oxadiazolo[3,4-e]pyrazin-5-yl)}amine (BAM15) is a new mitochondrial uncoupler protects mitochondria with more specificity and less cytotoxicity than other uncouplers. Kenwood et al. (Mol. Metab. 2013) demonstrated that BAM15 treatment improved renal outcomes after renal ischemia/reperfusion injury. We evaluated the therapeutic potential of BAM15 for sepsis AKI.

Methods

Cecal ligation and puncture (CLP) was performed to 10-week-old CD-1 mouse to induce sepsis. BAM15 (5mg/kg, i.p.) was injected 0 hours after CLP. We also evaluated kidney injury and systemic organ damage and inflammation 18 hours after CLP. A survival study was conducted with both early (0hrs) and delayed (6hrs) BAM15 treatmement.

Results

BAM15 treatment at the time of CLP surgery improved both survival (fifteen of twenty of non-treatment group and five of twenty of treatment group were died in 7days: P<0.05) and kidney function at 18 hours along with reduced tubular histological damage, tubular hypoxia, systemic inflammation (e.g. IL-6 and IL-10) and splenic apoptosis (a marker of late immunosuppression), but did not improve other organs (e.g. liver and muscle). Furthermore, delayed treatment of BAM15 (6 hours after CLP) also improved survival (seventeen of twenty of non-treatment group and ten of eighteen of treatment group were died in 7days: P<0.05) and kidney dysfunction after sepsis.

Conclusion

Sepsis increased mitochondrial damage, tubular hypoxia, renal histological damage and, accelerated splenic apoptosis and systemic inflammation resulting in AKI and death. BAM15 significantly attenuated these processes, improved survival, and selectively improved septic AKI.

Funding

  • NIDDK Support