Abstract: FR-OR103
Inability to Regulate Fatty Acid Oxidation or Glycolysis Increases Renal Fibrosis
Session Information
- Signaling in CKD Progression
October 26, 2018 | Location: 23A, San Diego Convention Center
Abstract Time: 04:42 PM - 04:54 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Lee, Mardiana, Austin Health, Melbourne, Victoria, Australia
- Mount, Peter F., Austin Health, Melbourne, Victoria, Australia
- Katerelos, Marina, Austin Health, Melbourne, Victoria, Australia
- Gleich, Kurt, Austin Health, Melbourne, Victoria, Australia
- Power, David A., Austin Health, Melbourne, Victoria, Australia
Background
Changes in energy metabolism are emerging as a key contributor to renal fibrosis. Expression of genes regulating fatty acid metabolism is reduced in fibrotic kidneys and aerobic glycolysis increases in some renal disease models. We aimed to determine the role of phosphorylation events that control fatty acid oxidation (FAO) and glycolysis in renal fibrosis.
Methods
The folic acid nephropathy (FAN) and unilateral ureteric obstruction (UUO) models were induced in mice with knock-in mutations of phosphosites in acetyl CoA carboxylase 1 and 2 (ACC1/2KI mice), the major regulator of FAO, and 6-phosphofructo-2kinase/fructose-2,6-biphosphatase (PFKFB2KI mice), the major regulator of glycolysis. Metformin, which activates AMPK to increase phosphorylation of ACC and PFKFB2, was administered to mice with FAN.
Results
ACC Ser79 phosphorylation was reduced in folate-treated tubular epithelial cells (p<0.01) and WT mice with FAN (p<0.05). Mutation of these sites in ACC1/2 KI mice with FAN or UUO caused lipid accumulation (Oil Red O p<0.01), increased triglyceride (p<0.01), increased collagen (PicroSirius red p<0.001; Masson’s Trichrome p<0.01; qRT-PCR p<0.01) and increased α-SMA (Western blot p<0.05; qRT-PCR p<0.01). Metformin administration was associated with reduced fibrosis (PicroSirius red p<0.01) and lipid accumulation (Oil Red O p<0.05) in WT mice, but not in ACC1/2KI mice. To determine the role of control of glycolysis, UUO was induced in PFKFB2KI mice. WT mice with UUO had reduced PFKFB2 Ser483 phosphorylation (p<0.01). PFKFB2KI UUO mice had increased collagen (Picrosirius red p<0.001), increased fibronectin (Western blot p<0.05; qRT-PCR p<0.05), increased α-SMA (Western blot, p<0.05) (Fig.1) and glycogen accumulation (PAS, p<0.05).
Conclusion
These data suggest that reduced phosphorylation of ACC and PFKFB2 are deleterious following renal injury. Drugs that reverse this, such as metformin, may be useful in preventing and treating renal fibrosis.
Western blot analysis showing increased expression of α-SMA in PFKKI UUO mice. *P<0.05, ***P<0.001
Funding
- Other NIH Support