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Persistent activation of dermal fibroblasts from patients with gadolinium-associated nephrogenic systemic fibrosis
  1. Sonsoles Piera-Velazquez1,
  2. Natalia Louneva1,2,
  3. Jolanta Fertala1,
  4. Peter J Wermuth1,
  5. Francesco Del Galdo1,3,
  6. Sergio A Jimenez1
  1. 1Department of Dermatology and Cutaneous Biology, Division of Connective Tissue Diseases, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
  2. 2Department of Psychiatry, Center for Neurobiology and Behavior, Translation Research Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  3. 3Head of Scleroderma Programme, Section of Musculoskeletal Diseases, Leeds Institute of Molecular Medicine, Leeds University, Leeds, UK
  1. Correspondence to Dr Sergio A Jimenez, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, 233 South, 10th Street, Suite 509 BLSB, Philadelphia, PA 19107, USA; sergio.jimenez{at}jefferson.edu

Abstract

Background Nephrogenic systemic fibrosis (NSF) is a systemic fibrotic disorder occurring in some patients with renal insufficiency after exposure to gadolinium-based contrast agents (GdBCA).

Objectives To examine cultured NSF dermal fibroblast production and expression of collagens I and III, fibronectin, hyaluronic acid and α-smooth muscle actin (α-SMA) during serial passages and the effects of two GdBCA on collagen gene expression and production by normal dermal fibroblasts.

Methods NSF fibroblasts were analysed for expression and production of types I and III collagen, fibronectin, hyaluronic acid and α-SMA. Collagen, type I, α1 (COL1A1) promoter transcription was examined in transient transfections. Nuclear extracts were assayed for binding activity of 108 transcription factors, and specific transcription factor binding was examined by electrophoretic gel mobility assays. Normal fibroblasts were cultured with GdBCA, and collagen expression assessed by real-time PCR and western blots.

Results NSF fibroblasts displayed a marked increase in collagens I and III, fibronectin and hyaluronic acid production, which was maintained for 9–11 subpassages in vitro. NSF fibroblasts also showed a marked increase in α-SMA expression, twofold higher transcriptional activity of the COL1A1 promoter and increased cREL binding in nuclear extracts compared with normal fibroblasts. GdBCA induced a dose-dependent stimulation of COL1A1 expression and production of type I collagen in normal fibroblasts.

Conclusions Fibroblasts from patients with NSF displayed a markedly profibrotic phenotype, which was maintained for several passages in culture. Elevated COL1A1 expression was mediated by transcriptional activation of its promoter associated with increased cREL binding activity. GdBCA stimulated cultured normal fibroblasts to produce increased amounts of collagen.

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Footnotes

  • SP-V and NL contributed equally to this work

  • Funding The contributions of SAJ, SP-V, NL and JF were supported by NIH/NIAMS grant RO1 AR019616 to SAJ. FDG was supported by a Dermatology Foundation Career Development Award and a Scleroderma Foundation grant. PJW was supported by NIAMS training grant T-32 AR007583-15.

  • Ethics approval This study was conducted with the approval of the Thomas Jefferson University Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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