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Mutation of regulatory phosphorylation sites in PFKFB2 worsens renal fibrosis
- Source :
- Scientific Reports, Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group UK, 2020.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Nephrology
medicine.medical_specialty
Phosphofructokinase-2
Blotting, Western
lcsh:Medicine
Diseases
urologic and male genital diseases
Kidney
Biochemistry
Article
Nephropathy
03 medical and health sciences
Mice
0302 clinical medicine
Fibrosis
Internal medicine
medicine
Renal fibrosis
Animals
Glycolysis
Phosphorylation
lcsh:Science
Cells, Cultured
Multidisciplinary
Kinase
Chemistry
lcsh:R
medicine.disease
Mice, Mutant Strains
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Mutation
lcsh:Q
Kidney Diseases
030217 neurology & neurosurgery
Homeostasis
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....8ca9cfe0cf130641d795bb3ce0f2cbdc