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Kidney Week

Abstract: SA-PO159

Peroxisomal Inhibition Abolishes Dicarboxylic Acid-Mediated AKI Protection

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Silva Barbosa, Anne Caroline, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Pfister, Katherine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Chiba, Takuto, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Uhlean, Rebecca Magen, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Schilling, Birgit, Buck Institute for Research on Aging, Novato, California, United States
  • Goetzman, Eric S., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Sims-Lucas, Sunder, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Peroxisomes play important roles in metabolism, including in fatty acid oxidation (FAO). Interestingly, post-translational modification of lysine residues by succinylation promotes FAO and has also been linked to acute kidney injury (AKI). In addition, octanedioic acid (DC8) is a dicarboxylic acid that, upon FAO, promotes hypersuccinylation. Finally, studies suggest that 10,12-tricosadiynoyl-CoA (TDYA) inhibits peroxisomal activity. Therefore, we hypothesized that DC8 protects from AKI via hypersuccinylation of renal peroxisomes and that TDYA blocks this response.

Methods

To test the role of DC8 in AKI, mice were fed with control or 10% w/w DC8 diet, then, subjected to unilateral renal ischemia-reperfusion (IRI). Six days after IRI, mice underwent contralateral nephrectomy and were euthanized the following day. Supplementation was provided until sacrifice. To test if TDYA would promote an opposite response, we treated another cohort of animals with or without daily doses of 2mg/kg TDYA for 18 days. On the third day, animals began being fed on 10% DC8 and underwent IRI as previously. Biochemical, histologic, and proteomic analyses were performed together with mitochondrial and peroxisomal activities.

Results

DC8 prevented the rise of renal injury markers in IRI mice and improved morphology compared with controls, demonstrating efficient protection against AKI. Proteomics evidenced a substantial increase in peroxisomal succinylation in DC8-fed animals, which was confirmed by immunofluorescence and peroxisomal FAO activity, while mitochondrial activity was shown to be preserved. Furthermore, TDYA completely abolished all the protective responses of DC8 as it inhibited peroxisomal activity.

Conclusion

DC8 supplementation drives renal hypersuccinylation, promoting a shift from mitochondrial to peroxisomal FAO, and protecting against AKI. Meanwhile, peroxisomal inhibition with TDYA completely inhibits this protection and confirms the important role of peroxisomal succinylation in AKI protection following DC8 administration.