Abstract: PO0440
Inability to Increase Fatty Acid Oxidation Worsens AKI and Impacts the Benefit of Metformin
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
- 103 AKI: Mechanisms
Authors
- Harley, Geoffrey, Austin Health, Heidelberg, Victoria, Australia
- Katerelos, Marina, Austin Health, Heidelberg, Victoria, Australia
- Gleich, Kurt, Austin Health, Heidelberg, Victoria, Australia
- Power, David A., Austin Health, Heidelberg, Victoria, Australia
- Mount, Peter F., Austin Health, Heidelberg, Victoria, Australia
Background
Energy metabolism is critical to the pathogenesis of ischaemic acute kidney injury (AKI) - its role in nephrotoxic AKI is less understood. Fatty acid oxidation (FAO), the kidney's most important energy source, is regulated by acetyl-CoA carboxylase (ACC). Metformin increases FAO by increasing phosphorylation of ACC. We aimed to determine whether regulation of FAO affects the outcome of nephrotoxic AKI.
Methods
Cisplatin AKI was induced in ACC knockin (KI) mice, which have mutations of ACC phospho-sites that disrupt FAO regulation, and compared to wild-type (WT) controls. A primary tubular epithelial cell (TEC) culture model of cisplatin toxicity was used to further study the findings.
Results
ACC KI mice demonstrated more severe cisplatin-AKI versus WT as assessed by day 2 serum urea (ACC KI 40.5+11.6 mM vs WT 27.2+7.6 mM, p <0.005) and creatinine (ACC KI 0.09+0.03 mM vs WT 0.06+0.03 mM, p <0.05). Western blot for neutrophil gelatinase associated lipocalin (NGAL) was increased 9.3+2.1 fold in ACC KI compared to 3.3+3.4 fold in WT (p<0.0001 for ACC KI vs WT). WT and ACC KI TEC cultures exposed to cisplatin revealed increased apoptosis in ACC KI, as assessed by increased cleaved caspase-3 (cCasp3) (p<0.0001). In TECs, metformin was protective against cisplatin mediated apoptosis, however this was diminished in ACC KI cells (cCasp3 reduced 49.5%) versus WT cells (cCasp3 reduced 72%) (p=0.03 for ACC KI vs WT).
Conclusion
Severity of nephrotoxic AKI is dependent on maintaining regulation of FAO. Metformin reduces cisplatin-AKI severity by its ability to increase FAO.
Funding
- Government Support – Non-U.S.