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

Eur J Pharmacol. 1999 Aug 20;379(1):97-106. doi: 10.1016/s0014-2999(99)00447-1.

Abstract

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.

MeSH terms

  • Animals
  • Blotting, Northern
  • Calcium / physiology
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • Cyclosporine / pharmacology*
  • Egtazic Acid / pharmacology
  • Endothelin-1 / genetics*
  • Endothelium / drug effects*
  • Female
  • Fluorometry
  • Galactosidases / metabolism
  • Genes, Reporter / drug effects*
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Luciferases / genetics
  • Plasmids
  • Pregnancy
  • RNA, Messenger / metabolism*
  • Rats
  • Transfection
  • Umbilical Veins / drug effects
  • Umbilical Veins / metabolism

Substances

  • Chelating Agents
  • Endothelin-1
  • Immunosuppressive Agents
  • RNA, Messenger
  • Egtazic Acid
  • Cyclosporine
  • Luciferases
  • Galactosidases
  • Calcium