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.
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