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Aquaporin 1 and 5 expression decreases during human intervertebral disc degeneration: Novel HIF-1-mediated regulation of aquaporins in NP cells
Johnson, ZI Gogate, SS Day, R Binch, A Markova, DZ Chiverton, N Cole, A Shapiro, IM Le Maitre, CL Risbud, MV
Johnson, ZI
Gogate, SS
Day, R
Binch, A
Markova, DZ
Chiverton, N
Cole, A
Shapiro, IM
Le Maitre, CL
Risbud, MV
Editors
Other contributors
Affiliation
Epub Date
Issue Date
2015-03-20
Submitted date
Subjects
Animals
Humans
Rats
Microscopy, Fluorescence
Blotting, Western
Immunohistochemistry
Chromatin Immunoprecipitation
Transfection
Cell Hypoxia
Gene Expression Regulation
Response Elements
Aquaporin 1
Aquaporin 5
Hypoxia-Inducible Factor 1, alpha Subunit
Real-Time Polymerase Chain Reaction
Intervertebral Disc Degeneration
Humans
Rats
Microscopy, Fluorescence
Blotting, Western
Immunohistochemistry
Chromatin Immunoprecipitation
Transfection
Cell Hypoxia
Gene Expression Regulation
Response Elements
Aquaporin 1
Aquaporin 5
Hypoxia-Inducible Factor 1, alpha Subunit
Real-Time Polymerase Chain Reaction
Intervertebral Disc Degeneration
Alternative
Abstract
Objectives of this study were to investigate whether AQP1 and AQP5 expression is altered during intervertebral disc degeneration and if hypoxia and HIF-1 regulate their expression in NP cells. AQP expression was measured in human tissues from different degenerative grades; regulation by hypoxia and HIF-1 was studied using promoter analysis and gain- and loss-of-function experiments. We show that both AQPs are expressed in the disc and that mRNA and protein levels decline with human disease severity. Bioinformatic analyses of AQP promoters showed multiple evolutionarily conserved HREs. Surprisingly, hypoxia failed to induce promoter activity or expression of either AQP. While genomic chromatin immunoprecipitation showed limited binding of HIF-1α to conserved HREs, their mutation did not suppress promoter activities. Stable HIF-1α suppression significantly decreased mRNA and protein levels of both AQPs, but HIF-1α failed to induce AQP levels following accumulation. Together, our results demonstrate that AQP1 and AQP5 expression is sensitive to human disc degeneration and that HIF-1α uniquely maintains basal expression of both AQPs in NP cells, independent of oxemic tension and HIF-1 binding to promoter HREs. Diminished HIF-1 activity during degeneration may suppress AQP levels in NP cells, compromising their ability to respond to extracellular osmolarity changes.
Citation
Johnson, Z. I., Gogate, S. S., Day, R., Binch, A., Dessislava Z. M., Chiverton, N., Cole, A., Conner, M., Shapiro, I. M., Le Maitre, C. L. and Risbud, M. V. (2015) Aquaporin 1 and 5 expression decreases during human intervertebral disc degeneration: Novel HIF-1-mediated regulation of aquaporins in NP cells, Oncotarget, 6(14), pp. 11945-11958.
Publisher
Journal
Research Unit
PubMed ID
25844601
PubMed Central ID
Embedded videos
Type
Journal article
Language
en
Description
Series/Report no.
ISSN
EISSN
1949-2553
ISBN
ISMN
Gov't Doc #
Sponsors
This work is supported by grants from the National Institutes of Health AR055655, AR064733 and AR050087 (MVR). Zariel I. Johnson is supported by T32 AR052273.
Rights
Licence for published version: Creative Commons Attribution 4.0 International