Open AccessLiver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling
Author(s) -
Seyhan H.,
Hamzavi J.,
Wiercinska Eliza,
Gressner A. M.,
Mertens P. R.,
Kopp J.,
Horch R. E.,
Breitkopf Katja,
Dooley S.
Publication year - 2006
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2006.tb00535.x
Subject(s) - hepatic stellate cell , cholestasis , transdifferentiation , smad , biology , signal transduction , western blot , smad2 protein , blot , hepatic fibrosis , sirius red , immunohistochemistry , fibrosis , downregulation and upregulation , medicine , pathology , endocrinology , cancer research , microbiology and biotechnology , immunology , biochemistry , stem cell , gene
Background/Aims: Profibrogenic TGF‐β signaling in hepatic stellate cells is modulated during transdifferentiation. Strategies to abrogate TGF‐β effects provide promising antifibrotic results, however, in vivo data regarding Smad activation during fibrogenesis are scarce. Methods: Here, liver fibrosis was assessed subsequent to bile duct ligation by determining liver enzymes in serum and collagen deposition in liver tissue. Activated hepatic stellate cells were identified by immunohistochemistry and immunoblots for alpha smooth muscle actin. Cellular localization of Smad3 and Smad7 proteins was demonstrated by immunohistochemistry. RTPCR for Smad4 and Smad7 was conducted with total RNA and Northern blot analysis for Smad7 with mRNA. Whole liver lysates were prepared to detect Smad2/3/4 and phospho‐ Smad2/3 by Western blotting. Results: Cholestasis induces TGF‐β signaling via Smad3 in vivo , whereas Smad2 phosphorylation was only marginally increased. Smad4 expression levels were unchanged. Smad7 expression was continuously increasing with duration of cholestasis. Hepatocytes of fibrotic lesions exhibited nuclear staining Smad3. In contrast to this, Smad7 expression was localized to activated hepatic stellate cells. Conclusions: Hepatocytes of damaged liver tissue display increased TGF‐β signaling via Smad3. Further, negative feedback regulation of TGF‐β signaling by increased Smad7 expression in activated hepatic stellate cells occurs, however does not interfere with fibrogenesis.