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TGFβ modulates cell-cell communication in early epithelial-to-mesenchymal transition
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Hills, Claire E., Siamantouras, Eleftherios, Smith, S. W., Cockwell, Paul, Liu, Kuo-Kang and Squires, Paul E. (2012) TGFβ modulates cell-cell communication in early epithelial-to-mesenchymal transition. Diabetologia, Vol.55 (No.3). pp. 812-824. doi:10.1007/s00125-011-2409-9 ISSN 0012-186X.
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Official URL: http://dx.doi.org/10.1007/s00125-011-2409-9
Abstract
Aims/hypothesis A key pathology in diabetic nephropathy is tubulointerstitial fibrosis.
Characterized by increased deposition of the extracellular matrix, fibrotic scar formation and
declining renal function, the prosclerotic cytokine TGF-β1 mediates many of these catastrophic
changes. The current study investigates a role for TGF-β1 induced epithelial to mesencyhmal
transition (EMT) in alterations in cell-adhesion, cell coupling and cell communication in the
human renal proximal tubule.
Methods: Whole-cell and cell-compartment expression of E-cadherin, N-cadherin, Snail,
vimentin, β-catenin and connexin-43 (Cx43) was determined in HK2 and human proximal tubule
cells (hPTC) +/-TGF-β1, using western blotting and immunocytochemistry, and quantified using
densitometry. The contribution of Cx43 in PT cell communication was quantified using small
interfering RNA knockdown, whilst dye-transfer assessed gap-junction mediated intercellular
communication (GJIC). Functional tethering was assessed by single-cell force spectroscopy +/-
TGF-β1 or immunoneutralization of cadherin ligation.
Results: High glucose (25mmol/l) increased the secretion of TGF-β1 from HK2 cells. Analysis
confirmed early TGF-β1 induced morphological and phenotypic changes of EMT with altered
expression of adhesion and adheren junction proteins. These changes correlated with impaired cell
adhesion and decreased tethering between coupled cells. Impaired E-cadherin mediated adhesion
induced a loss of Cx43 expression and GJIC, an effect mimicked by neutralizing E-cadherin
ligation. Up-regulation of N-cadherin failed to restore adhesion or Cx43 mediated GJIC.
Conclusions: Our study provides compelling evidence that TGF-β1 induced EMT instigates a loss
in E-cadherin, cell adhesion and ultimately connexin-mediated cell communication in the
proximal tubule under diabetic conditions ahead of overt signs of renal damage.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QP Physiology | ||||
Divisions: | Faculty of Science, Engineering and Medicine > Engineering > Engineering Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
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Library of Congress Subject Headings (LCSH): | Diabetic nephropathies -- Pathogenesis, Kidneys -- Fibrosis, Cytokines | ||||
Journal or Publication Title: | Diabetologia | ||||
Publisher: | Springer | ||||
ISSN: | 0012-186X | ||||
Official Date: | 4 March 2012 | ||||
Dates: |
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Volume: | Vol.55 | ||||
Number: | No.3 | ||||
Number of Pages: | 13 | ||||
Page Range: | pp. 812-824 | ||||
DOI: | 10.1007/s00125-011-2409-9 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access | ||||
Date of first compliant deposit: | 18 December 2015 | ||||
Date of first compliant Open Access: | 18 December 2015 | ||||
Funder: | Diabetes UK, Diabetes Research & Wellness Foundation (DRWF), European Foundation for the Study of Diabetes (EFSD), Janssen Pharmaceutical Ltd., University of Warwick Research Development Fund, Wellcome Trust (London, England) | ||||
Grant number: | BDA:11/0004215 (DUK) |
Data sourced from Thomson Reuters' Web of Knowledge
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