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


METHODS
Observational study.


METHODS
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.


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


METHODS
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.


CONCLUSIONS
Small patient cohort.


CONCLUSIONS
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.
Schieren
Gisela
G
Department of Nephrology, University Hospital, Heinrich-Heine University Düsseldorf, Germany. gisela.schieren@med.uni-duesseldorf.de
Gambichler
Thilo
T
Skrygan
Marina
M
Burkert
Björn
B
Altmeyer
Peter
P
Rump
Lars Christian
LC
Kreuter
Alexander
A
D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D015331:Cohort Studies; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D054989:Nephrogenic Fibrosing Dermopathy / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D006435:Renal Dialysis; D012595:Scleroderma, Systemic / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D012333:RNA, Messenger; D051899:Smad2 Protein; D051900:Smad3 Protein; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D055513:Connective Tissue Growth Factor