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Kidney Week

Abstract: TH-PO102

Metabolic Reprogramming in Sepsis-Associated AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Li, Ying, University of California, San Diego, Santee, California, United States
  • Singh, Prabhleen, UC San Diego & VA San Diego Healthcare System, San Diego, California, United States
Background

AKI significantly contributes to the morbidity and mortality. Therapeutic strategies are limited due to incomplete understanding of its pathogenesis. Changes in tubular metabolism in response to cellular stress during sepsis may play an important role. A sepsis-associated AKI (s-AKI) model induced by cecal ligation and puncture (CLP) was used to investigate the early and late changes in mitochondrial function and tubular metabolism in s-AKI.

Methods

C57bl/6 mice underwent CLP or sham surgery. Mitochondrial biogenesis, content and dynamics were examined at 4 hours (4 h’) and 24 hours (24 h’) post CLP. Mitochondrial respiration is freshly isolated proximal tubules was examined with XF96 Seahorse analyzer. Expression of glycolytic enzymes and other assays of tublar metabolism were performed. Lastly, the role of AMP-activated protein kinase (AMPK), the principal cellualr metabolic sensor, was also investigated.

Results

Mitochondrial DNA copy number, PGC1α and Tfam expression were increased at 4 h’ but significantly decreased at 24h’ post-CLP. Mitochondrial fusion proteins were unchanged at 4' but decreased significantly at 24h’ in CLP kidneys. Basal respiration in proximal tubules was significantly diminished in CLP at 4h’. At 24h’, a significantly increased maximum respiration rate was observed, suggesting a shift to glycolytic metabolism. The expression of phosphofructokinase (PFK), a rate-limiting glycolytic enzyme, was significantly elevated, while carnitine palmitoyltransferase I (CPT1), a rate-limiting enzyme of lipid oxidation, was dramatically reduced at 24h’. Treatment with AICAR, an AMPK activator, prevented CLP-induced alteration of mitochondrial function (dynamics and biogenesis) and improved GFR.

Conclusion

Our novel findings demonstrate early changes in mitochondrial function and metabolic preprogramming in s-AKI. Mitochondrial dysfunction with a shift to glycolytic metabolism with dimished fatty oxidation under cellular stress is seen. Activation of AMPK improves mitochondrial function by improving mitochondrial biogenesis and fusion. Additional effects on tubular metabolic reprogramming with AMPK activation is being investigated.

Funding

  • NIDDK Support