Balance of profibrotic and antifibrotic [corrected] signaling in nephrogenic systemic fibrosis skin lesions.

Abstract

BACKGROUND:

Nephrogenic systemic fibrosis (NSF) is an uncommon fibrotic disorder occurring after administration of linear gadolinium contrast agents in patients with severely decreased kidney function. The underlying pathogenetic mechanism of fibrosis remains to be elucidated. Transforming growth factor beta (TGF-beta), a key player in the pathogenesis of fibrotic disorders, has been found to be overexpressed in NSF skin lesions. The aim of this study is to analyze the TGF-beta-SMAD-connective tissue growth factor (CTGF) axis in NSF skin lesions compared with skin specimens from patients with systemic sclerosis, hemodialysis patients without NSF, and healthy controls. Additionally, expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and antifibrotic tumor necrosis factor alpha (TNF-alpha) were examined.

STUDY DESIGN:

Observational study.

SETTING & PARTICIPANTS:

Full-thickness skin biopsy specimens from fibrotic lesions or healthy skin were obtained from 10 patients with NSF, 16 patients with systemic sclerosis, 8 non-NSF hemodialysis patients, and 17 healthy participants.

PREDICTOR:

Patient diagnosis of NSF, systemic sclerosis, non-NSF hemodialysis patients, and healthy participants, as defined using skin biopsy.

OUTCOME & MEASUREMENTS:

Dermal messenger RNA and protein expression of profibrotic TGF-beta, SMAD2, SMAD3, SMAD4, SMAD7, CTGF, TIMP-1, antifibrotic SMAD7, and TNF-alpha were analyzed using real-time reverse transcription-polymerase chain reaction and immunohistologic examination on formalin-embedded tissue.

RESULTS:

Dermal expression of nearly all parameters differed in hemodialysis patients compared with healthy controls. In comparison to hemodialysis patients and healthy participants, we found increased messenger RNA levels for TGF-beta, the profibrotic receptor-activated SMAD2 and SMAD3, CTGF, and TIMP-1 in NSF and systemic sclerosis lesions. Few differences between NSF and non-NSF hemodialysis patients were observed for common SMAD4, inhibitory SMAD7, and TNF-alpha.

LIMITATIONS:

Small patient cohort.

CONCLUSION:

Our results suggest a profibrotic imbalance in the TGF-beta-SMAD-CTGF axis in NSF skin lesions. Significantly increased dermal expression of TGF-beta and TIMP-1 in non-NSF hemodialysis patients in comparison to healthy participants emphasizes the need for a hemodialysis control group for future investigations and suggests a pre-existing profibrotic situation in the skin of hemodialysis patients.

• Authors: Gisela Schieren, Thilo Gambichler, Marina Skrygan, Björn Burkert, Peter Altmeyer, Lars Christian Rump, Alexander Kreuter
• Journal: American journal of kidney diseases : the official journal of the National Kidney Foundation (Am J Kidney Dis) Vol. 55 Issue 6 Pg. 1040-9 (Jun 2010) ISSN: 1523-6838 [Electronic] United States
• PMID: 20430497 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• RNA, Messenger
• Smad2 Protein
• Smad3 Protein
• Tissue Inhibitor of Metalloproteinase-1
• Transforming Growth Factor beta
• Tumor Necrosis Factor-alpha
• Connective Tissue Growth Factor

Topics

• Aged
• Aged, 80 and over
• Biopsy
• Cohort Studies
• Connective Tissue Growth Factor (metabolism)
• Female
• Humans
• Kidney Diseases (metabolism, pathology, therapy)
• Male
• Middle Aged
• Nephrogenic Fibrosing Dermopathy (metabolism, pathology)
• RNA, Messenger (metabolism)
• Renal Dialysis
• Scleroderma, Systemic (metabolism, pathology)
• Signal Transduction (physiology)
• Skin (metabolism, pathology)
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)
• Transforming Growth Factor beta (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)