HARLEY G1, KATERELOS M1, GLEICH K1, POWER D1,2, MOUNT P1,2
1Austin Health, Melbourne, Australia, 2University of Melbourne, Melbourne, Australia
Aim: To determine whether regulation of fatty acid oxidation (FAO) affects the outcome of acute kidney injury (AKI).
Background: Energy metabolism is critical to the pathogenesis of ischaemic AKI, but its role in nephrotoxic AKI is less understood. FAO, the most important energy source in the kidney, is regulated by acetyl-CoA carboxylase (ACC). Metformin increases FAO in cells by increasing phosphorylation of ACC.
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 compared to 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 the injury marker 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). Primary ACC KI and WT 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 effect was diminished in ACC KI cells (cCasp3 reduced 49.5%) compared to the WT cells (cCasp3 reduced 72%) (p=0.03 for ACC KI vs WT).
Conclusion: The severity of nephrotoxic AKI is dependent on maintaining regulation of FAO. Metformin reduces the severity of cisplatin-induced injury by its ability to increase FAO.
Bio to come.