Title: Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling
Abstract: Journal of Cellular and Molecular MedicineVolume 10, Issue 4 p. 922-932 Open Access Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling H. Seyhan, H. Seyhan Department of Plastic and Hand Surgery, University Medical Center Erlangen, GermanySearch for more papers by this authorJ. Hamzavi, J. Hamzavi Center of Molecular Alcohol Research, II. Medical Clinic, Faculty of Medicine Mannheim, University of Heidelberg, GermanySearch for more papers by this authorEliza Wiercinska, Eliza Wiercinska Center of Molecular Alcohol Research, II. Medical Clinic, Faculty of Medicine Mannheim, University of Heidelberg, GermanySearch for more papers by this authorA. M. Gressner, A. M. Gressner Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, GermanySearch for more papers by this authorP. R. Mertens, P. R. Mertens Department of Clinical Immunology and Nephrology, RWTH University Hospital Aachen, GermanySearch for more papers by this authorJ. Kopp, J. Kopp Department of Plastic and Hand Surgery, University Medical Center Erlangen, GermanySearch for more papers by this authorR. E. Horch, R. E. Horch Department of Plastic and Hand Surgery, University Medical Center Erlangen, GermanySearch for more papers by this authorKatja Breitkopf, Katja Breitkopf Center of Molecular Alcohol Research, II. Medical Clinic, Faculty of Medicine Mannheim, University of Heidelberg, GermanySearch for more papers by this authorS. Dooley, Corresponding Author S. Dooley Center of Molecular Alcohol Research, II. Medical Clinic, Faculty of Medicine Mannheim, University of Heidelberg, Germany Correspondence to: Steven DOOLEY Department of Medicine II, Gastroenterology and Hepatology, University Hospital, Theodor-Kutzer Ufer 1-3, 68135 Mannheim, Germany. Tel.: 0049-621-383-3768 E-mail: [email protected]Search for more papers by this author H. Seyhan, H. Seyhan Department of Plastic and Hand Surgery, University Medical Center Erlangen, GermanySearch for more papers by this authorJ. Hamzavi, J. Hamzavi Center of Molecular Alcohol Research, II. Medical Clinic, Faculty of Medicine Mannheim, University of Heidelberg, GermanySearch for more papers by this authorEliza Wiercinska, Eliza Wiercinska Center of Molecular Alcohol Research, II. Medical Clinic, Faculty of Medicine Mannheim, University of Heidelberg, GermanySearch for more papers by this authorA. M. Gressner, A. M. Gressner Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, GermanySearch for more papers by this authorP. R. Mertens, P. R. Mertens Department of Clinical Immunology and Nephrology, RWTH University Hospital Aachen, GermanySearch for more papers by this authorJ. Kopp, J. Kopp Department of Plastic and Hand Surgery, University Medical Center Erlangen, GermanySearch for more papers by this authorR. E. Horch, R. E. Horch Department of Plastic and Hand Surgery, University Medical Center Erlangen, GermanySearch for more papers by this authorKatja Breitkopf, Katja Breitkopf Center of Molecular Alcohol Research, II. Medical Clinic, Faculty of Medicine Mannheim, University of Heidelberg, GermanySearch for more papers by this authorS. Dooley, Corresponding Author S. Dooley Center of Molecular Alcohol Research, II. Medical Clinic, Faculty of Medicine Mannheim, University of Heidelberg, Germany Correspondence to: Steven DOOLEY Department of Medicine II, Gastroenterology and Hepatology, University Hospital, Theodor-Kutzer Ufer 1-3, 68135 Mannheim, Germany. Tel.: 0049-621-383-3768 E-mail: [email protected]Search for more papers by this author First published: 09 October 2008 https://doi.org/10.1111/j.1582-4934.2006.tb00535.xCitations: 25AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract 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. 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