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Am J Physiol Cell Physiol (July 9, 2003). doi:10.1152/ajpcell.00105.2003
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Submitted on March 19, 2003
Accepted on July 2, 2003

Gene Expression Profile of Endothelin-1-Induced Growth in Glomerular Mesangial Cells

Rangnath Mishra1, Patrick Leahy1, and Michael S Simonson1*

1 Medicine, Case Western Reserve University, Cleveland, OH, USA

* To whom correspondence should be addressed. E-mail: mss5{at}po.cwru.edu.

Endothelin-1 (ET-1) is a vasoconstrictor and mitogen involved in vascular remodeling. Changes in gene expression that underlie control of cell growth by ET-1 remain poorly characterized. To identify pathways of growth control we used microarrays to analyze ET-1-regulated gene expression in human mesangial cells, an important ET-1 vascular target cell in vivo. Statistical assessment of differential expression (significance analysis of microarrays) revealed up-regulated transcripts for growth factors (HBEGF, FGF, IL6) and down-regulated transcripts for genes that inhibit growth (BAX, p27KIP1, DAD1). Consistent with the gene expression profile, quantitative RT-PCR and Western blotting confirmed induction of heparin-binding EGF-like growth factor (HB-EGF) by ET-1. To test a functional role for HB-EGF in ET-1 signaling, we showed that exogenous HB-EGF stimulated phosphorylation of ErbB1 and growth of mesangial cells. ET-1-induced proliferation was blocked by an ErbB1 receptor-selective kinase inhibitor and by a specific ErbB1 receptor neutralizing antibody. Proliferation in response to ET-1 was also inhibited by neutralizing antisera against human HB-EGF. Taken together, these results provide data for modeling ET-1 pathways for growth control and suggest a specific role for HB-EGF gene induction in mesangial cell growth in response to ET-1.




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