Cyclosporin A induces prepro endothelin-1 gene transcription in human endothelial cells

Cyclosporin A employed in treatment of organ allograft rejection, is associated with hypertension possibly due to endothelin-1. We studied transcriptional regulation of endothelin-1 by cyclosporin A in human endothelial cells using cell transfection experiments and reporter gene assays. Human umbilical vein endothelial cells were established expressing a fusion gene of the coding sequence of the firefly luciferase gene, placed under the control of the rat endothelin-1 promoter. Luciferase assays demonstrate 2.8-fold stimulation of the reporter gene by cyclosporin A (P < 0.01), and Northern blot analysis shows induction of prepro endothelin-1 mRNA. Transcription is tightly repressed in the absence of the immunosuppressant, its regulation occurs Ca(2+)-dependent. Lack of extra- or intracellular Ca2+ prevents cyclosporin A-dependent endothelin-1 gene transcription and mRNA induction. These data demonstrate transcriptional regulation of endothelin-1 over a range of several orders of magnitude in human umbilical vein endothelial cells by cyclosporin A via Ca(2+)-dependent mechanisms. They support the critical role of endothelin- in cyclosporin A-associated hypertension.