INABILITY TO REGULATE FATTY ACID OXIDATION OR GLYCOLYSIS INCREASES RENAL FIBROSIS

M LEE1,2, P MOUNT1, M KATERELOS1, K GLEICH1, D POWER1,2
1Austin Health, Heidelberg, Australia, 2Department of Medicine, The University of Melbourne, Heidelberg, Australia

Aim: To determine the roles of fatty acid oxidation (FAO) and glycolysis in renal fibrosis.
Background: Changes in energy metabolism are emerging as a key contributor in renal fibrosis. Expression of genes regulating fatty acid metabolism is reduced in fibrotic kidneys and aerobic glycolysis increases in renal disease models.
Methods: 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, were used to assess the roles of FAO and glycolysis, respectively. The folic acid nephropathy (FAN) and unilateral ureteric obstruction (UUO) models were induced in male ACC1/2KI and PFKFB2KI mice. Metformin 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 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) and glycogen accumulation (PAS, p<0.05).
Conclusions: These data suggest reduced FAO and glycolysis is deleterious following renal injury. Phosphorylation of ACC reduces renal fibrosis and is essential for the anti-fibrotic effect of metformin.


Biography:
Mardiana Lee completed her advanced training in nephrology through  the Austin and the Royal Melbourne Hospital. She received her fellowship from the Royal Australasian College of Physician in 2015. She is currently completing her PhD at the University of Melbourne.

About ANZSN

The ASM is hosted by Australian and New Zealand Society of Nephrology.

The aims of the Society are to promote and support the study of the kidney and urinary tract in health and disease, and to ensure the highest professional standards for the practice of nephrology in Australia and New Zealand.

Conference Managers

Please contact the team at Conference Design with any questions regarding the Annual Scientific Meeting

© 2015 - 2016 Conference Design Pty Ltd