Sci Rep. 2020 Sep 3;10(1):14531. doi: 10.1038/s41598-020-71475-z.
Mutation of regulatory phosphorylation sites in PFKFB2 worsens renal fibrosis
Kidney Laboratory, Department of Nephrology, Austin Health, Heidelberg, VIC, 3084, Australia. Department of Medicine, The University of Melbourne, Heidelberg, VIC, Australia. Mater Research Institute-the University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia. Glycation, Nutrition and Metabolism Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia. The Institute for Breathing and Sleep (IBAS), Austin Health, Heidelberg, VIC, Australia. Kidney Laboratory, Department of Nephrology, Austin Health, Heidelberg, VIC, 3084, Australia. Department of Medicine, The University of Melbourne, Heidelberg, VIC, Australia. The Institute for Breathing and Sleep (IBAS), Austin Health, Heidelberg, VIC, Australia.
Service type: Knock-in mice
Fatty acid oxidation is the major energy pathway used by the kidney, although glycolysis becomes more important in the low oxygen environment of the medulla. Fatty acid oxidation appears to be reduced in renal fibrosis, and drugs that reverse this improve fibrosis. Expression of glycolytic genes is more variable, but some studies have shown that inhibiting glycolysis reduces renal fibrosis. To address the role of glycolysis in renal fibrosis, we have used a genetic approach. The crucial control point in the rate of glycolysis is 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase. Phosphorylation of the kidney isoform, PFKFB2, on residues Ser468 and Ser485 stimulates glycolysis and is the most important mechanism regulating glycolysis. We generated transgenic mice with inactivating mutations of Ser468 and Ser485 in PFKFB2 (PFKFB2 KI mice). These mutations were associated with a reduced ability to increase glycolysis in primary cultures of renal tubular cells from PFKFB2 KI mice compared to WT cells. This was associated in PFKFB2 KI mice with increased renal fibrosis, which was more severe in the unilaternal ureteric obstruction (UUO) model compared with the folic acid nephropathy (FAN) model. These studies show that phosphorylation of PFKFB2 is important in limiting renal fibrosis after injury, indicating that the ability to regulate and maintain adequate glycolysis in the kidney is crucial for renal homeostasis. The changes were most marked in the UUO model, probably reflecting a greater effect on distal renal tubules and the greater importance of glycolysis in the distal nephron.View Publication