Abstract: SA-PO120
The Role of Glycolysis in Progression of Renal Fibrosis
Session Information
- AKI: Mechanisms - AKI-CKD Transition
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Harley, Geoffrey, Austin Health, Melbourne, Victoria, Australia
- Lee, Mardiana, Austin Health, Melbourne, Victoria, Australia
- Katerelos, Marina, Austin Health, Melbourne, Victoria, Australia
- Gleich, Kurt, Austin Health, Melbourne, Victoria, Australia
- Sullivan, Mitchell A., Mater Research Institute - The University of Queensland, Brisbane, New South Wales, Australia
- Mount, Peter F., Austin Health, Melbourne, Victoria, Australia
- Power, David A., Austin Health, Melbourne, Victoria, Australia
Background
Fatty acid oxidation is reduced in renal fibrosis and drugs that increase it improve fibrosis. The role of glycolysis, however, is unclear. We mutated a key controller of glycolysis in mice to determine its effect on renal fibrosis.
Methods
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) is a key regulator of glycolysis. Mice with inactivating S466A and S483A mutations of the phosphorylation sites in PFKFB2 (PFKFB2 KI mice) were generated. The mutations are predicted to reduce the ability to increase the rate of glycolysis following stimulation. The unilateral ureteric obstruction (UUO) and folic acid nephropathy (FAN) models were used.
Results
In both UUO (p<0.01) and FAN (p<0.05) models, there was reduced expression of PFKFB2 in WT mice compared with controls. PFKFB2 KI mice showed no obvious phenotype and had normal plasma glucose. Serum creatinine and urea were similar to wild type (WT). Western blots confirmed unchanged levels of PFKFB2 expression in kidneys from PFKFB2 KI mice. In the UUO model, there were significant increases in renal fibrosis in PFKFB2 KI mice when assessed by picrosirius red staining (p<0.001), RT-PCR and Western blots for a-SMA (p<0.05) and fibronectin (p<0.05) compared to WT. Glycogen increased similarly in both KI and WT mice following UUO but lipid accumulation, measured by oil red O (p<0.005), was greater in PFKFB2 KI mice. In contrast, similar studies with the FAN model showed no significant increase in fibrosis, greater glycogen content in the PFKFB2 KI mice compared to WT (p<0.05) and no difference in lipid accumulation.
Conclusion
These data show that inhibition of the regulation of glycolysis by PFKFB2 increases fibrosis in the UUO but not the FAN model. Increased fibrosis in the UUO model may reflect a greater effect on distal tubules compared with the FAN model, with the well-known reliance of distal tubules on glycolysis leading to energy shortage and fibrosis.
Funding
- Government Support - Non-U.S.