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Kidney Week

Abstract: PO0449

Succinylation of Metabolic Enzymes Protects Against AKI

Session Information

  • AKI: Novel Insights
    November 04, 2021 | Location: On-Demand, Virtual Only
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 101 AKI: Epidemiology, Risk Factors, and Prevention

Authors

  • Pfister, Katherine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Sims-Lucas, Sunder, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Acute Kidney Injury (AKI) is an increasingly prevalent outcome of hospitalizations, affecting up to 50% of ICU patients in America. Kidney function depends on the metabolic activity of Renal Proximal Tubule Epithelial Cells (RPTECs). To understand AKI pathology, we focused on a class of proteins that affect posttranslational modifications of major proteins, and especially the deacylase Sirtuin 5 which is highly expressed in RPTECs. Our previous studies indicate that knockout of this protein has a protective role in RPTECs post AKI which presents the exciting possibility of clinical translation in preventing or ameliorating any long-term damage from AKI.

Methods

Through independent pathway analysis and mass spectrometry we attributed the major protective effect of Sirt5 knockout to be succinylation of key mitochondrial and peroxisomal proteins, leading to a metabolic shift from mitochondrial Fatty Acid Oxidation (FAO) to peroxisomal-dependent FAO.
To test this hypothesis in a less invasive manner than genetic knockdown, we used the mitochondrial FAO inhibitor Etomoxir and the peroxisomal stimulator Benzifibrate. In both cases we found a significant reduction in the kidney injury marker NGAL after ischemia-like injury.

Results

We postulate that the switch to more peroxisomal-mediated fatty acid oxidation is protective due to a decrease in the Reactive Oxygen Species. To promote this shift, we investigated the effects of supplementing the mouse diet with medium-chain fatty acids (10% dodecanedioic acid) pre or post ischemia-reperfusion-injury (IRI). Mass spectrometry of the succinylation signature of murine kidneys after diet treatment was similar to that of the Sirt5 KO mice, suggesting a functional phenocopy. We have preliminary evidence that there is less oxidative stress when the dodecanedioic acid diet is administered pre- or post-injury and there is less overall damage to the proximal tubule epithelia.

Conclusion

The data from these experiments suggest a simple but effective diet treatment could reduce the burden of AKI cases.

Funding

  • NIDDK Support