Kidney Week

Abstract: FR-PO138

Dicarboxylic Acid Supplementation Protects Mice From AKI via Increased Renal Peroxisomal Activity

Session Information

• AKI: Mechanisms - II
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  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

Anne Caroline Silva Barbosa,

• Pfister, Katherine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Katherine Pfister,

• Chiba, Takuto, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Takuto Chiba,

• Goetzman, Eric S., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Eric S. Goetzman,

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

Sunder Sims-Lucas,

Background

Lysine succinylation is a posttranslational modification associated with the control of acute kidney injury (AKI). Hypersuccinylation favors peroxisomal fatty acid oxidation (FAO) instead of mitochondrial. In addition, the medium-chain fatty acids dodecanedioic acid (DC₁₂) and octanedioic acid (DC₈), upon FAO, originate succinyl-CoA, a succinylation co-factor.

Methods

To test the roles of medium-chain fatty acids during AKI, mice were fed with a control, a 10% w/w DC₁₂, or 10% w/w DC₈ diet, then, subjected to two models of AKI, unilateral renal ischemia-reperfusion (IRI), or an in-bolus cisplatin injection (20mg/kg). Supplementation was provided until sacrifice. Cisplatin animals were euthanized 3 days after injury, whereas IRI mice underwent contralateral nephrectomy on day 6 and were euthanized on day 7. Biochemical, histologic, genetic, and proteomic analyses were performed; the latter involving a lysine-succinylome-based mass spectrometry (LSMS).

Results

DC₁₂ prevented the rise of serum creatinine, blood urea nitrogen, and renal injury markers in mice during both models of AKI as well as improved morphology compared with controls. However, DC₈ was even more protective against AKI than DC₁₂. Intriguingly, while DC₈ promotes succinylation in the kidneys only, DC₁₂promotes it in both the liver and kidneys. Finally, LSMS evidenced that, regardless of surgical status, the kidneys of DC₁₂- and DC₈-fed mice showed, respectively, mild and extensive upregulation of a myriad of peroxisomal activity-related peptides, and a decline in mitochondrial FAO in comparison to control-fed mice.

Conclusion

DC₈ or DC₁₂ supplementation drives renal hypersuccinylation, promoting a shift from mitochondrial to peroxisomal fatty acid oxidation, and protecting against AKI. Dicarboxylic acid supplementation is convenient, inexpensive, easily administered, and efficient in preventing AKI. We believe this study could be translated in the future to the clinical setting, which would highly benefit the high-risk population.