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Persistent activation of dermal fibroblasts from patients with gadolinium-associated nephrogenic systemic fibrosis.
- Source :
-
Annals of the rheumatic diseases [Ann Rheum Dis] 2010 Nov; Vol. 69 (11), pp. 2017-23. Date of Electronic Publication: 2010 Jun 22. - Publication Year :
- 2010
-
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).<br />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.<br />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.<br />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.<br />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.
- Subjects :
- Actins biosynthesis
Cells, Cultured
Collagen biosynthesis
Collagen Type I biosynthesis
Collagen Type I genetics
Collagen Type I, alpha 1 Chain
Contrast Media pharmacology
Dose-Response Relationship, Drug
Fibroblasts drug effects
Fibronectins biosynthesis
Gadolinium pharmacology
Gene Expression Regulation drug effects
Humans
Hyaluronic Acid biosynthesis
Nephrogenic Fibrosing Dermopathy metabolism
Nephrogenic Fibrosing Dermopathy pathology
RNA, Messenger genetics
Skin pathology
Contrast Media adverse effects
Fibroblasts metabolism
Gadolinium adverse effects
Nephrogenic Fibrosing Dermopathy chemically induced
Skin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1468-2060
- Volume :
- 69
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Annals of the rheumatic diseases
- Publication Type :
- Academic Journal
- Accession number :
- 20570839
- Full Text :
- https://doi.org/10.1136/ard.2009.127761