title: Endothelin-1 induces NF-kappaB via two independent pathways in human renal tubular epithelial cells.
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-kappaB 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-kappaB-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-kappaB 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-kappaB 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.
  
  
  CONCLUSIONS
  Thus prohibiting ET-1-mediated gene transcription necessitates blocking of NF-kappaB and diacylglycerol signal transduction in proximal tubule cells.
authors: Department of Pathology, University of Cologne, Cologne, Germany.
authors: Melanie
authors: M
authors: Gerstung
authors: Tanja
authors: T
authors: Roth
authors: Hans-Peter
authors: HP
authors: Dienes
authors: Christoph
authors: C
authors: Licht
authors: Jochen W U
authors: JW
authors: Fries
mesh_terms: D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D004075:Diglycerides; D019332:Endothelin-1; D016328:NF-kappa B; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B