Document Detail


Epithelial-mesenchymal transition and fibrosis are mutually exclusive reponses in shear-activated proximal tubular epithelial cells.
MedLine Citation:
PMID:  22744866     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Renal fibrosis (RF) is thought to be a direct consequence of dedifferentiation of resident epithelial cells via an epithelial-mesenchymal transition (EMT). Increased glomerular flow is a critical initiator of fibrogenesis. Yet, the responses of proximal tubular epithelial cells (PTECs) to fluid flow remain uncharacterized. Here, we investigate the effects of pathological shear stresses on the development of fibrosis in PTECs. Our data reveal that type I collagen accumulation in shear-activated PTECs is accompanied by a ∼40-60% decrease in cell motility, thus excluding EMT as a relevant pathological process. In contrast, static incubation of PTECs with TGFβ1 increases cell motility by ∼50%, and induces stable expression of key mesenchymal markers, including Snail1, N-cadherin, and vimentin. Ectopic expression of TGFβ1 in shear-activated PTECs fails to induce EMT-associated changes but abrogates collagen accumulation via SMAD2-dependent mechanisms. Shear-mediated inhibition of EMT occurs via cyclic oscillations in both ERK2 activity and downstream expression of EMT genes. A constitutive ERK2 mutant induces stable expression of Snail1, N-cadherin, and vimentin, and increases cell motility in shear-activated PTECs by 250% without concomitant collagen deposition. Collectively, our data reveal that RF not only occurs without EMT but also that these two responses represent mutually exclusive cell fates.
Authors:
Bryan M Grabias; Konstantinos Konstantopoulos
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-28
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  26     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-02     Completed Date:  2012-12-12     Revised Date:  2013-10-11    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4131-41     Citation Subset:  IM    
Affiliation:
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, New Engineering Bldg. 114, 3400 N. Charles St., Baltimore, MD 21218, USA.
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MeSH Terms
Descriptor/Qualifier:
Blotting, Western
Cell Line
Cell Movement / drug effects,  genetics
Collagen Type I
Enzyme-Linked Immunosorbent Assay
Epithelial Cells / cytology*,  drug effects,  metabolism*
Epithelial-Mesenchymal Transition / drug effects,  physiology*
Fibrosis / metabolism,  pathology*
Fluorescent Antibody Technique
Humans
Kidney Tubules, Proximal / cytology*
Reverse Transcriptase Polymerase Chain Reaction
Transfection
Transforming Growth Factor beta1 / pharmacology
Grant Support
ID/Acronym/Agency:
R01 AR053358/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Collagen Type I; 0/Transforming Growth Factor beta1
Comments/Corrections

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