| 1. |
- Nilsson, Daniel, 1975, et al.
(författare)
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Foxc2 is essential for podocyte function.
- 2019
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Ingår i: Physiological reports. - : Wiley. - 2051-817X. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- Foxc2 is one of the earliest podocyte markers during glomerular development. To circumvent embryonic lethal effects of global deletion of Foxc2, and to specifically investigate the role of Foxc2 in podocytes, we generated mice with a podocyte-specific Foxc2 deletion. Mice carrying the homozygous deletion developed early proteinuria which progressed rapidly into end stage kidney failure and death around postnatal day 10. Conditional loss of Foxc2 in podocytes caused typical characteristics of podocyte injury, such as podocyte foot process effacement and podocyte microvillus transformation, probably caused by disruption of the slit diaphragm. These effects were accompanied by a redistribution of several proteins known to be necessary for correct podocyte structure. One target gene that showed reduced glomerular expression was Nrp1, the gene encoding neuropilin 1, a protein that has been linked to diabetic nephropathy and proteinuria. We could show that NRP1 was regulated by Foxc2 invitro, but podocyte-specific ablation of Nrp1 in mice did not generate any phenotype in terms of proteinuria, suggesting that the gene might have more important roles in endothelial cells than in podocytes. Taken together, this study highlights a critical role for Foxc2 as an important gene for podocyte function.
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| 2. |
- Rotter Sopasakis, Victoria, 1972, et al.
(författare)
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Elevated Glucose Levels Preserve Glucose Uptake, Hyaluronan Production, and Low Glutamate Release Following Interleukin-1 beta Stimulation of Differentiated Chondrocytes
- 2019
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Ingår i: Cartilage. - : SAGE Publications. - 1947-6035 .- 1947-6043. ; 10:4, s. 491-503
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Tidskriftsartikel (refereegranskat)abstract
- Objective Chondrocytes are responsible for remodeling and maintaining the structural and functional integrity of the cartilage extracellular matrix. Because of the absence of a vascular supply, chondrocytes survive in a relatively hypoxic environment and thus have limited regenerative capacity during conditions of cellular stress associated with inflammation and matrix degradation, such as osteoarthritis (OA). Glucose is essential to sustain chondrocyte metabolism and is a precursor for key matrix components. In this study, we investigated the importance of glucose as a fuel source for matrix repair during inflammation as well as the effect of glucose on inflammatory mediators associated with osteoarthritis. Design To create an OA model, we used equine chondrocytes from 4 individual horses that were differentiated into cartilage pellets in vitro followed by interleukin-1 beta (IL-1 beta) stimulation for 72 hours. The cells were kept at either normoglycemic conditions (5 mM glucose) or supraphysiological glucose concentrations (25 mM glucose) during the stimulation with IL-1 beta. Results We found that elevated glucose levels preserve glucose uptake, hyaluronan synthesis, and matrix integrity, as well as induce anti-inflammatory actions by maintaining low expression of Toll-like receptor-4 and low secretion of glutamate. Conclusions Adequate supply of glucose to chondrocytes during conditions of inflammation and matrix degradation interrupts the detrimental inflammatory cycle and induces synthesis of hyaluronan, thereby promoting cartilage repair.
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| 3. |
- Sakaguchi, M., et al.
(författare)
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FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- A major target of insulin signaling is the FoxO family of Forkhead transcription factors, which translocate from the nucleus to the cytoplasm following insulin-stimulated phosphorylation. Here we show that the Forkhead transcription factors FoxK1 and FoxK2 are also downstream targets of insulin action, but that following insulin stimulation, they translocate from the cytoplasm to nucleus, reciprocal to the translocation of FoxO1. FoxK1/FoxK2 translocation to the nucleus is dependent on the Akt-mTOR pathway, while its localization to the cytoplasm in the basal state is dependent on GSK3. Knockdown of FoxK1 and FoxK2 in liver cells results in upregulation of genes related to apoptosis and down-regulation of genes involved in cell cycle and lipid metabolism. This is associated with decreased cell proliferation and altered mitochondrial fatty acid metabolism. Thus, FoxK1/K2 are reciprocally regulated to FoxO1 following insulin stimulation and play a critical role in the control of apoptosis, metabolism and mitochondrial function.
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| 4. |
- Sukonina, Valentina, et al.
(författare)
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FOXK1 and FOXK2 regulate aerobic glycolysis.
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 566, s. 279-283
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Tidskriftsartikel (refereegranskat)abstract
- Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
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