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Vol. 27, No. 3, 2007
Issue release date: May 2007
Section title: Original Report: Laboratory Investigation
Am J Nephrol 2007;27:294–300
(DOI:10.1159/000101999)

Endothelin-1 Induces NF-κB via Two Independent Pathways in Human Renal Tubular Epithelial Cells

Gerstung M. · Roth T. · Dienes H.-P. · Licht C. · Fries J.W.U.
aDepartment of Pathology, University of Cologne, Cologne, Germany, and bDivision of Nephrology, Hospital for Sick Children, Toronto, Ont., Canada

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Article / Publication Details

First-Page Preview
Abstract of Original Report: Laboratory Investigation

Received: 1/23/2007
Accepted: 3/19/2007
Published online: 4/25/2007

Number of Print Pages: 7
Number of Figures: 4
Number of Tables: 0

ISSN: 0250-8095 (Print)
eISSN: 1421-9670 (Online)

For additional information: http://www.karger.com/AJN

Abstract

Background: Endothelin-1 (ET-1) is a major transcriptional activator of renal proximal tubule cells acting in an autocrine and paracrine manner. In animal studies, ET-1 has been implicated in progressive renal interstitial fibrosis by promoting gene expression, possibly via the inflammatory NF-ĸB signal pathway. While ET-1-dependent mechanisms of signal transduction have been studied mainly in tumor cell lines, we analyzed the mechanism of ET-1-induced, NF-ĸB-mediated target gene activation in proximal tubule cells. Methods: Human renal proximal tubule cells were stimulated with ET-1 and gene expression analyzed by protein microarray, Western blot, non-radioactive electromobility shift assay, and quantitative real-time polymerase chain reaction. Results: Activation of NF-ĸB occurs only via an ET-1-specific type A receptor (not type B as in animals). Induction can be blocked by bosentan, and endothelin-A but not endothelin-B receptor-specific antagonists. Protein microarray screening shows activation of two independent cascades (via the endothelin-A receptor, or via diacylglycerol) leading to NF-ĸB induction. The independent induction is also reflected by target gene expression such as the vascular cell adhesion molecule-1, interleukin-6, and fractalkine at different time points. Conclusion: Thus prohibiting ET-1-mediated gene transcription necessitates blocking of NF-ĸB and diacylglycerol signal transduction in proximal tubule cells.


  

Author Contacts

Dr. Jochen W.U. Fries, MD
Division of Molecular Nephropathology, Department of Pathology
University of Cologne, Joseph-Stelzmann-Strasse 9
DE–50931 Cologne (Germany)
Tel. +49 221 478 6061, Fax +49 221 478 6360, E-Mail jochen.fries@uni-koeln.de

  

Article Information

This work was supported by a grant from the Imhoff-Stiftung, in part from a post-doctoral fellowship from the Cologne Fortune program of the University of Cologne to C.L., and private donations. M.G. is the recipient of a doctoral research fellowship from the Cologne Fortune program of the University of Cologne.

Received: January 23, 2007
Accepted: March 19, 2007
Published online: April 25, 2007
Number of Print Pages : 7
Number of Figures : 4, Number of Tables : 0, Number of References : 31

  

Publication Details

American Journal of Nephrology

Vol. 27, No. 3, Year 2007 (Cover Date: May 2007)

Journal Editor: Bakris, G. (Chicago, Ill.)
ISSN: 0250–8095 (print), 1421–9670 (Online)

For additional information: http://www.karger.com/AJN


Article / Publication Details

First-Page Preview
Abstract of Original Report: Laboratory Investigation

Received: 1/23/2007
Accepted: 3/19/2007
Published online: 4/25/2007

Number of Print Pages: 7
Number of Figures: 4
Number of Tables: 0

ISSN: 0250-8095 (Print)
eISSN: 1421-9670 (Online)

For additional information: http://www.karger.com/AJN


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