Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Spasic, Maja Vujic^1,5  Sparla, Richard^1,5  Mleczko-Sanecka, Katarzyna^1,5  Migas, Mary C.²  Breitkopf-Heinlein, Katja³  Dooley, Steven³  Vaulont, Sophie⁴  Fleming, Robert E.²  Muckenthaler, Martina U.^1,5 

[1] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[2] St Louis Univ, Sch Med, Dept Pediat, St Louis, MO 63104 USA

[3] Univ Hosp Mannheim, Dept Mol Hepatol Alcohol Associated Dis 2, Mannheim, Germany

[4] Univ Paris 05, CNRS, INSERM, U1016,Inst Cochin,UMR8104, F-75270 Paris, France

[5] Univ Heidelberg Hosp, MMPU, Heidelberg, Germany

关键词: Smad6;    Smad7;    Hepcidin;    Hemochromatosis;    Iron;    Bmp/Smad;   

DOI  :  10.1016/j.bbadis.2012.08.013

来源: Elsevier

【 摘 要 】

The inhibitory Smad7 acts as a critical suppressor of hepcidin, the major regulator of systemic iron homeostasis. In this study we define the mRNA expression of the two functionally related Smad proteins, Smad6 and Smad7, within pathways known to regulate hepcidin levels. Using mouse models for hereditary hemochromatosis (Hfe-, TfR2-, Hfe/TIR2-, Hjv- and hepcidin1-deficient mice) we show that hepcidin, Smad6 and Smad7 mRNA expression is coordinated in such a way that it correlates with the activity of the Bmp/Smad signaling pathway rather than with liver iron levels. This regulatory circuitry is disconnected by iron treatment of Hfe-/- and Hfe/TfR2 mice that significantly increases hepatic iron levels as well as hepcidin, Smad6 and Smad7 mRNA expression but fails to augment pSmad1/5/8 levels. This suggests that additional pathways contribute to the regulation of hepcidin, Smad6 and Smad7 under these conditions which do not require Hfe. (C) 2012 Elsevier B.V. All rights reserved.

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