Decorin Is Significantly Overexpressed in Nephrogenic Systemic Fibrosis

Department of Dermatology and Allergology, Ruhr-University Bochum, Bochum, Germany.
American Journal of Clinical Pathology (Impact Factor: 3.01). 07/2009; 132(1):139-43. DOI: 10.1309/AJCPGB55YDURJXZC
Source: PubMed

ABSTRACT The role of the proteoglycans in the pathogenesis of nephrogenic systemic fibrosis (NSF) is unclear. We assessed expression of decorin, versican, and transforming growth factor beta1 (TGF-beta1) in skin specimens of 10 patients with biopsy-proven NSF and different control groups. Real-time reverse transcription-polymerase chain reaction studies and immunohistochemical analysis were performed on full-thickness skin specimens. The messenger RNA (mRNA) and protein levels of decorin were significantly higher in the skin lesions of patients with NSF than in skin lesions of patients with systemic sclerosis, patients undergoing hemodialysis, and healthy subjects. The versican mRNA levels in NSF lesions differed significantly only from the levels in healthy subjects. TGF-beta1 mRNA expression was significantly overexpressed in NSF lesions compared with control skin specimens investigated. In NSF specimens, the mRNA expression of TGF-beta1 and decorin were highly correlated (r = 0.92). Our results suggest that decorin and TGF-beta1 may have a fundamental role in the pathogenesis of NSF. Conversely, versican seems less likely to be of pathogenetic significance in NSF.

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    ABSTRACT: 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. Observational study. 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. Patient diagnosis of NSF, systemic sclerosis, non-NSF hemodialysis patients, and healthy participants, as defined using skin biopsy. 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. 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. Small patient cohort. 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.
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    ABSTRACT: Mesangial matrix expansion is a prominent feature of the most common form of glomerulonephritis, IgA nephropathy (IgAN). To find molecular markers and improve the understanding of the disease, the gene and protein expression of proteoglycans were investigated in biopsies from IgAN patients and correlated to clinical and morphological data. We collected and microdissected renal biopsies from IgAN patients (n = 19) and from healthy kidney donors (n = 14). Patients were followed for an average time of 4 years and blood pressure was according to target guidelines. Distinct patterns of gene expression were seen in glomerular and tubulo-interstitial cells. Three of the proteoglycans investigated were found to be of special interest and upregulated in glomeruli: perlecan, decorin and biglycan. Perlecan gene expression negatively correlated to albumin excretion and progress of the disease. Abundant decorin protein expression was found in sclerotic glomeruli, but not in unaffected glomeruli from IgAN patients or in controls. Transforming growth factor beta (TGF-β), known to interact with perlecan, decorin and biglycan, were upregulated both on gene and protein level in the glomeruli. This study provides further insight into the molecular mechanisms involved in mesangial matrix expansion in IgAN. We conclude that perlecan is a possible prognostic marker for patients with IgAN. In addition, the up-regulation of biglycan and decorin, as well as TGF-β itself, indicate that regulation of TGF-β, and other profibrotic markers plays a role in IgAN pathology.
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