Kidney Week

Abstract: TH-OR013

Sirtuin 5 Regulates a Metabolic Switch in Fatty Acid Oxidation That Protects Against AKI

Session Information

• AKI: Mechanisms - Injury and Repair
  November 07, 2019 | Location: Salon A/B, Walter E. Washington Convention Center
  Abstract Time: 04:54 PM - 05:06 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Peasley, Kevin, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Kevin Peasley

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

Takuto Chiba,

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

Elina Mukherjee,

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

Eric S. Goetzman,

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

Sunder Sims-Lucas,

Background

There are currently no targeted drug therapies for the treatment of acute kidney injury (AKI). The proximal tubule compartment is particularly vulnerable to injury, owing to high energy demands. Fatty acids are a preferred energy source for proximal tubule cells and are oxidized at high rates through both the mitochondrial and peroxisomal fatty acid oxidation (FAO) pathways. Sirtuins are a class of enzymes which reverse post-translational lysine acylation and regulate many biological processes including FAO. Multiple sirtuins, including 1, 3, and 6 have been shown to play roles in AKI, but the role of mitochondrial-based Sirtuin 5 (Sirt5) during AKI has yet to be determined.

Methods

Male germline Sirt5 deficient mice (either +/- or -/-) and wild-type controls at 8-12 weeks old were subjected to two different AKI models: 1. unilateral ischemia-reperfusion injury (22 minutes) or 2. single high dose cisplatin-induced AKI (20 mg/kg). Mice were evaluated for injury by histopathological analysis and by serum chemistry. FAO was measured by the catabolism of ¹⁴C-labeled palmitate to ¹⁴CO₂. Peroxisome-specific FAO was measured by inhibition of mitochondrial FAO via etomoxir (100uM). Primary mouse proximal tubule cells were isolated from Sirt5-/- or WT mice and exposed to 24 hours hypoxia (FiO₂ 1%) or treated with 20µM cisplatin for 24 hours. hPTEC cells were exposed to combined glucose-oxygen deprivation with or without Sirt5 siRNA knockdown and evaluated for cell death by LDH efflux.

Results

No overt kidney phenotype was observed in Sirt5-/- mice at baseline. However, following IRI and cisplatin-induced AKI, Sirt5-/- and Sirt5+/- mice had significantly improved kidney function and less evidence of tissue injury compared with controls. The cell-based assays confirmed that knockdown of Sirt5 in proximal tubule cells was protective against both types of injury. This protection coincided with increased peroxisomal FAO and decreased mitochondrial FAO in the Sirt5-/- proximal tubules.

Conclusion

Subsequently, SIRT5 deficiency confers protection against multiple models of acute kidney injury. This identifies a therapeutically attractive mechanism whereby increased peroxisomal FAO and decreased mitochondrial FAO drives protection of kidneys from injury.