Gene expression profile of endothelin-1-induced growth in glomerular mesangial cells.

Endothelin (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 upregulated transcripts for growth factors [heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), fibroblast growth factor (FGF), interleukin (IL)-6] and downregulated transcripts for genes that inhibit growth (BAX, p27KIP1, DAD1). Consistent with the gene expression profile, quantitative RT-PCR and Western blotting confirmed induction of 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. 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.