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Published VersionCC BY V4.0, Open Access
Journal article
Mutation of regulatory phosphorylation sites in PFKFB2 worsens renal fibrosis
Scientific Reports, Vol.10, pp.1-12
2020
PMID: 32884050
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 Ser(468) and Ser(485) stimulates glycolysis and is the most important mechanism regulating glycolysis. We generated transgenic mice with inactivating mutations of Ser(468) and Ser(485) 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.
Details
- Title
- Mutation of regulatory phosphorylation sites in PFKFB2 worsens renal fibrosis
- Authors
- Mardiana Lee - Austin HealthGeoff Harley - Austin HealthMarina Katerelos - Austin HealthKurt Gleich - Austin HealthMitchell A Sullivan - The University of QueenslandAdrienne Laskowski - Monash UniversityMelinda T Coughlan - Monash UniversityScott A. Fraser - Austin HealthPeter F. Mount - The University of MelbourneDavid Power (Corresponding Author) - Austin Health
- Publication details
- Scientific Reports, Vol.10, pp.1-12
- Publisher
- Nature Publishing Group
- Date published
- 2020
- DOI
- 10.1038/s41598-020-71475-z
- ISSN
- 2045-2322
- PMID
- 32884050
- Copyright note
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Organisation Unit
- School of Health - Biomedicine
- Language
- English
- Record Identifier
- 991035095302621
- Output Type
- Journal article
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- Biochemistry & Molecular Biology
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