Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload |
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| Authors: | Maja Vujić Spasić Richard Sparla Katarzyna Mleczko-Sanecka Mary C Migas Katja Breitkopf-Heinlein Steven Dooley Sophie Vaulont Robert E Fleming Martina U Muckenthaler |
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| Institution: | 1. Dept. of Pediatric Oncology, Hematology and Immunology, University Hospital of Heidelberg, Germany;2. Saint Louis University School of Medicine, Dept. of Pediatrics, St. Louis, USA;3. Dept. of Molecular Hepatology—Alcohol Associated Diseases II, University Hospital of Mannheim, Germany;4. INSERM, U1016, Institute Cochin, CNRS, UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France;5. Molecular Medicine Partnership Unit (MMPU), University Hospital of Heidelberg, Germany |
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| Abstract: | 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/TfR2-, 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. |
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