Role of endothelin-1/endothelin receptor signaling in fibrosis and calcification in nephrogenic systemic fibrosis

Exp Dermatol. 2014 Sep;23(9):664-9. doi: 10.1111/exd.12500.

Abstract

Nephrogenic systemic fibrosis (NSF) is characterized by systemic fibrosis and abnormal calcification in patients with severe renal dysfunction. It is considered that gadolinium (Gd)-containing contrast agents used for magnetic resonance imaging trigger the development of NSF. However, the causative role of Gd and the mechanism of Gd-induced fibrosis and calcification in NSF are unknown. Recently, it has been known that endothelin-1 (ET-1)/ET receptor (ETR) signalling regulates fibrosis and calcification. The objective was to elucidate the role of ET-1/ETR signalling in Gd-induced fibrosis and calcification in NSF. First, we demonstrated that Gd enhanced proliferation and calcification of human adipose tissue-derived mesenchymal stem cells (hMSC) in vitro. Next, we examined the expression of ET-1 and ETR-A in hMSC using proliferation or calcification assay. ET-1 and ETR-A expression in hMSC treated with Gd were elevated. ET-1/ETR signalling inhibitor, bosentan, inhibited Gd-induced proliferation and calcification of hMSC. In addition, bosentan inhibited Gd-induced phosphorylation of ERK and Akt in hMSC. Plasma ET-1 levels of the patients were significantly higher than these of normal individuals and systemic sclerosis patients. In immunofluorescence staining, the expression of ETR-A in fibroblasts in dermal fibrosis lesion of NSF was increased. We conclude that Gd induces proliferation and calcification of hMSC via enhancement of ET-1/ETR signalling. Our results contribute to understand the pathogenesis of NSF.

Keywords: calcification; endothelin-1; fibrosis; mesenchymal stem cells; nephrogenic systemic fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Bosentan
  • Calcinosis / etiology
  • Calcinosis / metabolism
  • Calcinosis / pathology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Contrast Media / adverse effects
  • Endothelin Receptor Antagonists / pharmacology
  • Endothelin-1 / blood
  • Endothelin-1 / metabolism*
  • Gadolinium / adverse effects
  • Humans
  • Magnetic Resonance Imaging / adverse effects
  • Male
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / pathology
  • Middle Aged
  • Nephrogenic Fibrosing Dermopathy / etiology
  • Nephrogenic Fibrosing Dermopathy / metabolism*
  • Nephrogenic Fibrosing Dermopathy / pathology
  • Receptor, Endothelin A / metabolism*
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology

Substances

  • Contrast Media
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Receptor, Endothelin A
  • Sulfonamides
  • Gadolinium
  • gadolinium chloride
  • Bosentan