Kidney Week

Abstract: TH-PO226

Deletion of Sirtuin-5 (Sirt5) Protects Mice Against Ischemia-Reperfusion Kidney Injury

Session Information

• AKI Basic: Cell Death and Biomarkers
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

• 001 AKI: Basic

Authors

• Goetzman, Eric S., Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States

Eric S. Goetzman,

• Maringer, Katherine V., Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States

Katherine V. Maringer,

• Bharathi, Sivakama S, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States

Sivakama S Bharathi,

• Mukherjee, Elina, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States

Elina Mukherjee,

• Sims-Lucas, Sunder, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States

Sunder Sims-Lucas,

Background

Sirtuin-5 (Sirt5) is a deacylase enzyme that reverses the post-translational succinylation of lysine residues. Sirt5 is highly expressed in the kidney. In liver Sirt5 promotes function of the respiratory chain and of the mitochondrial fatty acid oxidation (FAO) pathway. While mitochondrial FAO is a critical source of energy for the proximal tubule, the role of Sirt5 in regulating kidney FAO during acute kidney injury (AKI) has not been investigated.

Methods

Sirt5 knockout mice (Sirt5KO) were subjected to ischemia-reperfusion kidney injury followed by contralateral nephrectomy on Day 6 and tissue harvest on Day 7. The oxidation of ¹⁴C-palmitate was used to follow FAO. Immunofluorescence was used to visualize mitochondria and peroxisomes, the two intracellular sites of FAO, in proximal tubules. Kidney injury markers were assessed by immunofluorescence and real-time PCR.

Results

Sirt5KO kidneys had reduced mitochondrial staining and reduced mitochondrial FAO at baseline. Conversely, peroxisome staining and peroxisomal FAO were increased. Despite compromised mitochondrial function, Sirt5KO mice exhibited significant protection against AKI. Day 7 post-injury serum creatinine was significantly lower than in wild-type mice. Tissue staining indicated less tubular damage, less fibrosis, and less inflammation. There was markedly less expression of kidney injury molecule-1 (Kim1) and activated caspase-3. Day 7 wild-type tubules showed abundant mitochondrial staining but a near-complete loss of peroxisomes, while Sirt5KO tubules showed peroxisomes but a loss of mitochondria. Peroxisomal FAO in Sirt5KO kidney was several-fold higher than in wild-type kidney. Finally, we observed Sirt5 protein in purified wild-type kidney peroxisomes suggesting that Sirt5 may serve to coordinate FAO between intracellular compartments.

Conclusion

Deletion of Sirt5 limits kidney injury in response to ischemia-reperfusion, the opposite of what has been reported in in knockouts of other sirtuins such as Sirt1 and Sirt3. Absence of Sirt5 compromises mitochondria but stabilizes peroxisomes. Given previously published obserations that peroxisomal abundance is associated with better outcomes from AKI, we propose that metabolic switching from mitochondria to peroxisomes is the mechanism by which deletion of Sirt5 is beneficial during ischemia-reperfusion injury.

Funding

• NIDDK Support