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      Impaired erythropoietin synthesis in chronic kidney disease is caused by alterations in extracellular matrix composition

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          Renal fibrosis and anaemia are two of the most relevant events in chronic kidney disease. Fibrosis is characterized by the accumulation of extracellular matrix proteins in the glomeruli and tubular interstitium. Anaemia is the consequence of a decrease in erythropoietin production in fibrotic kidneys. This work analyses the possibility that the accumulation of abnormal collagens in kidney interstitium could be one of the mechanisms responsible for erythropoietin decreased synthesis. In renal interstitial fibroblast grown on collagen I, erythropoietin mRNA expression and HIF‐2α protein decreased, whereas focal adhesion kinase protein ( FAK) phosphorylation and proteasome activity increased, compared to cells grown on collagen IV. Proteasome inhibition or FAK inactivation in cells plated on collagen I restored erythropoietin and HIF‐2α expression. FAK inhibition also decreased the collagen I‐dependent proteasome activation. In a model of tubulointerstitial fibrosis induced by unilateral ureteral obstruction in mice, increased collagen I protein content and an almost complete disappearance of erythropoietin mRNA expression were observed in the ureteral ligated kidney with respect to the contralateral control. Interestingly, erythropoietin synthesis was recovered in obstructed mice treated with proteasome inhibitor. These data suggest that reduced kidney erythropoietin synthesis could be caused by the accumulation of abnormal extracellular matrix proteins.

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          Most cited references 46

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          HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

           M Ivan,  Theresa Kim,  A Salic (2001)
          HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.
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            A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.

            We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells. Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal. DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48. Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression. Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function. Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment. We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis.
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              Integrin signaling.

              Cells reside in a protein network, the extracellular matrix (ECM), which they secrete and mold into the intercellular space. The ECM exerts profound control over cells. The effects of the matrix are primarily mediated by integrins, a family of cell surface receptors that attach cells to the matrix and mediate mechanical and chemical signals from it. These signals regulate the activities of cytoplasmic kinases, growth factor receptors, and ion channels and control the organization of the intracellular actin cytoskeleton. Many integrin signals converge on cell cycle regulation, directing cells to live or die, to proliferate, or to exit the cell cycle and differentiate.

                Author and article information

                J Cell Mol Med
                J. Cell. Mol. Med
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                30 August 2017
                January 2018
                : 22
                : 1 ( doiID: 10.1111/jcmm.2018.22.issue-1 )
                : 302-314
                [ 1 ] Department of System Biology Universidad de Alcalá Alcalá de Henares Madrid Spain
                [ 2 ] REDinREN (Instituto de Salud Carlos III) Madrid Spain
                [ 3 ] IRSIN Instituto Reina Sofía de Investigaciones Nefrológicas Madrid Spain
                [ 4 ] Department of Physiology and Pharmacology Universidad de Salamanca Salamanca Spain
                [ 5 ] Centre for Tumour Biology Barts Cancer Institute Queen Mary University of London London UK
                [ 6 ] Department of Nephrology and Rheumatology University Medical Center Goettingen University Goettingen Goettingen Germany
                [ 7 ] Instituto de Investigaciones Biomédicas de Salamanca (IBSAL) Salamanca Spain
                [ 8 ] Research Unit and Nephrology Section Hospital Príncipe de Asturias and Department of Medicine Universidad de Alcalá Alcalá de Henares Madrid Spain
                Author notes
                [* ] Correspondence to: Gemma OLMOS

                E‐mail: gemma.olmos@ 123456uah.es

                © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 7, Tables: 0, Pages: 13, Words: 7849
                Funded by: Instituto de Salud Carlos III. Feder funds
                Award ID: PI13/02270, PI14/01939, PI13/00336, PI14/02075
                Funded by: Universidad de Alcala
                Award ID: CCG2013/BIO‐022
                Funded by: Feder funds Retic REDinREN
                Award ID: RD12/0021/0006 and RD12/0021/0032
                Funded by: Consortium Madrid
                Award ID: S2010/BMD‐2321
                Original Article
                Original Articles
                Custom metadata
                January 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:26.12.2017


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