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Kidney Week

Abstract: PO0369

Tubular MPC1 Deletion Protects from Glycerol-Induced Kidney Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Rauckhorst, Adam J., The University of Iowa Healthcare, Iowa City, Iowa, United States
  • Simoni, Aaron A., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Vasquez Martinez, Gabriela, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Bolek, Robin L., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Rastogi, Prerna, The University of Iowa Healthcare, Iowa City, Iowa, United States
  • Pabla, Navjot Singh P., The Ohio State University, Columbus, Ohio, United States
  • Spitz, Douglas R., The University of Iowa Healthcare, Iowa City, Iowa, United States
  • Taylor, Eric, The University of Iowa Healthcare, Iowa City, Iowa, United States
  • Zepeda-Orozco, Diana, Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Pyruvate fuels mitochondrial oxidation, scavenges H2O2, and regulates the glutathione and thioredoxin dependent antioxidant systems. Acute kidney injury (AKI) results in damaging oxidative stress and metabolic disruptions that are lessened upon pyruvate treatment. The specific mechanism by which pyruvate protects against AKI is unknown. We hypothesize that the Mitochondrial Pyruvate Carrier 1 (MPC1), which controls the cellular fate of pyruvate, plays a central role in AKI and injury recovery.

Methods

MPC1 was disrupted in tubular epithelial cells by generating Pax8Cre+/-Mpc1f/f (Tub-MPC1-KO) mice and was tested against Mpc1f/f (Tub-MPC1-WT) littermates. 13C-tracer and steady state metabolomics were performed in 4 hour-fasted mice. Rhabdomyolysis-induced AKI was initiated by injecting 10 ml/kg of 50% glycerol into the hind limb of Tub-MPC1-WT vs Tub-MPC1-KO mice and we evaluated toxicity and kidney function prospectively.

Results

13C enrichment into TCA cycle intermediates demonstrated decreased glucose-driven PDH- and PC-dependent pyruvate metabolism in Tub-MPC-KO mice. At steady state, this fueled adaptations in carbohydrate, fatty acid, and amino acid metabolism. Interestingly, pathway analysis identified glutathione metabolism as significantly altered in Tub-MPC1-KO. Glutathione biosynthetic precursors were decreased and NADPH/NADP was increased in Tub-MPC1-KO kidney. This implies that the renal redox environment was potentially primed to be better able to respond to renal oxidative stress. To test this idea, rhabdomyolysis-induced AKI was initiated by injecting Tub-MPC1-WT and Tub-MPC1-KO mice intramuscularly with glycerol. Following AKI, Tub-MPC1-KO mice lost less weight and had significantly decreased serum cystatin C and BUN compared to Tub-MPC1-WT mice.

Conclusion

In vivo disruption of tubular MPC1 results in metabolic changes that favor a reduced cellular environment and protects from glycerol induced AKI.

Funding

  • NIDDK Support