Smad7 deficiency decreases iron and haemoglobin through hepcidin up-regulation by multilayer compensatory mechanisms

Journal of Cellular and Molecular Medicine

Volumn 22, Issue 6, 2018, Pages 3035-3044

  An, Peng ^a,b   Wang, Hao ^a,b,c   Wu, Qian ^a,b   Wang, Jiaming ^a,b   Xia, Zhidan ^a,b   He, Xuyan ^a,b   Wang, Xinhui ^a,b   Chen, Yan ^d   Min, Junxia ^a,b   Wang, Fudi ^a,b,c  

^a CHINA AGRICULTURAL UNIVERSITY   (China)

^b ZHEJIANG UNIVERSITY   (China)

^c ZHENGZHOU UNIVERSITY   (China)

^d UNIVERSITY OF CHINESE ACADEMY OF SCIENCES   (China)

Author keywords

Bambi; follistatin; hepcidin; iron deficiency; Smad6; Smad7

Indexed keywords

FERROPORTIN; FERROPORTIN 1; FOLLISTATIN; HEMOGLOBIN; HEPCIDIN; IRON; PHOSPHORUS; SMAD1 PROTEIN; SMAD5 PROTEIN; SMAD6 PROTEIN; SMAD7 PROTEIN; SMAD8 PROTEIN; BAMBI PROTEIN, MOUSE; MEMBRANE PROTEIN; SMAD6 PROTEIN, MOUSE; SMAD7 PROTEIN, MOUSE; TRANSFORMING GROWTH FACTOR BETA;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BAMBI GENE; CELL ISOLATION; FST GENE; GENE OVEREXPRESSION; HEMOGLOBIN DETERMINATION; HOMEOSTASIS; IMMUNOHISTOCHEMISTRY; IRON BLOOD LEVEL; IRON DEFICIENCY ANEMIA; LIVER CELL; LIVER TISSUE; MOUSE; NONHUMAN; PLASMID; PRIORITY JOURNAL; PROTEIN DEFICIENCY; REAL TIME POLYMERASE CHAIN REACTION; RNA EXTRACTION; SMAD6 GENE; TGF BETA SIGNALING; UPREGULATION; WESTERN BLOTTING; ANIMAL; GENE EXPRESSION REGULATION; GENETICS; HUMAN; KNOCKOUT MOUSE; LIVER; METABOLISM; SEQUENCE ANALYSIS; SIGNAL TRANSDUCTION;

ANIMALS; FOLLISTATIN; GENE EXPRESSION REGULATION; HEMOGLOBINS; HEPATOCYTES; HEPCIDINS; HUMANS; IRON; LIVER; MEMBRANE PROTEINS; MICE; MICE, KNOCKOUT; SEQUENCE ANALYSIS, RNA; SIGNAL TRANSDUCTION; SMAD6 PROTEIN; SMAD7 PROTEIN; TRANSFORMING GROWTH FACTOR BETA;

EID: 85044362284     PISSN: 15821838     EISSN: None     Source Type: Journal    
DOI: 10.1111/jcmm.13546     Document Type: Article

References (45)

1. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806-7810.
2. Krause A, Neitz S, Mägert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480:147-150.
3. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-2093.
4. Fleming RER, Ponka PP. Iron overload in human disease. N Engl J Med. 2012;366:348-359.
5. Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 2003;361:669-673.
6. Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest. 2005;115:2180-2186.
7. Nemeth E, Roetto A, Garozzo G, et al. Hepcidin is decreased in TFR2 hemochromatosis. Blood. 2005;105:1803-1806.
8. Ruchala P, Nemeth E. The pathophysiology and pharmacology of hepcidin. Trends Pharmacol Sci. 2014;35:155-161.
9. Ganz T, Nemeth E. The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders. Hematology Am Soc Hematol Educ Program. 2011;2011:538-542.
10. Andriopoulos B Jr, Corradini E, Xia Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41:482-487.
11. Meynard D, Kautz L, Darnaud V, et al. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet. 2009;41:478-481.
12. Wang R-H, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2:399-409.
13. Steinbicker AU, Bartnikas TB, Lohmeyer LK, et al. Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. Blood. 2011;118:4224-4230.
14. Zhou XY, Tomatsu S, Fleming RE, et al. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA. 1998;95:2492-2497.
15. Huang FW, Pinkus JL, Pinkus GS, et al. A mouse model of juvenile hemochromatosis. J Clin Invest. 2005;115:2187-2191.
16. Ahmad KA, Ahmann JR, Migas MC, et al. Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol Dis. 2002;29:361-366.
17. Kawabata H, Fleming RE, Gui D, et al. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood. 2005;105:376-381.
18. Mleczko-Sanecka K, Casanovas G, Ragab A, et al. SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood. 2010;115:2657-2665.
19. Vujić Spasić M, Sparla R, Mleczko-Sanecka K, et al. Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload. Biochim Biophys Acta. 2013;1832:76-84.
20. Kautz L, Meynard D, Monnier A, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad 7, Id1, and Atoh8 in the mouse liver. Blood. 2008;112:1503-1509.
21. Chen Q, Chen H, Zheng D, et al. Smad7 is required for the development and function of the heart. J Biol Chem. 2009;284:292-300.
22. Finberg KE, Whittlesey RL, Andrews NC. Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. Blood. 2011;117:4590-4599.
23. Zhang Z, Zhang F, An P, et al. Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood. 2011;118:1912-1922.
24. Zhang F, Tao Y, Zhang Z, et al. Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses. Haematologica. 2012;97:1826-1835.
25. Wang Q, Jiang L, Wang J, et al. Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice. Hepatology. 2008;49:1166-1175.
26. Zhang Z, Zhang F, Guo X, et al. Ferroportin1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores in mice. Hepatology. 2012;56:961-971.
27. Trapnell C, Pachter L, Salzberg SL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009;25:1105-1111.
28. Trapnell C, Roberts A, Goff L, et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc. 2012;7:562-578.
29. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425:577-584.
30. Corradini E, Meynard D, Wu Q, et al. Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology. 2011;54:273-284.
31. Onichtchouk D, Chen YG, Dosch R, et al. Silencing of TGF-beta signalling by the pseudoreceptor BAMBI. Nature. 1999;401:480-485.
32. Iemura S, Yamamoto TS, Takagi C, et al. Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. Proc Natl Acad Sci USA. 1998;95:9337-9342.
33. Tojo M, Takebe A, Takahashi S, et al. Smad7-deficient mice show growth retardation with reduced viability. J Biochem. 2012;151:621-631.
34. Hamzavi J, Ehnert S, Godoy P, et al. Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in mice. J Cell Mol Med. 2008;12:2130-2144.
35. Li RG, Rosendahl A, Brodin G, et al. Deletion of exon I of SMAD7 in mice results in altered B cell responses. J Immunol. 2006;176:6777-6784.
36. Zhu L, Wang L, Wang X, et al. Hepatic deletion of Smad7 in mouse leads to spontaneous liver dysfunction and aggravates alcoholic liver injury. PLoS ONE. 2011;6:e17415.
37. Estrada KD, Wang W, Retting KN, et al. Smad7 regulates terminal maturation of chondrocytes in the growth plate. Dev Biol. 2013;382:375-384.
38. Finberg KE, Whittlesey RL, Fleming MD, et al. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood. 2010;115:3817-3826.
39. Nai A, Rubio A, Campanella A, et al. Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice. Blood. 2016;127:2327-2336.
40. Karaulanov E, Knochel W, Niehrs C. Transcriptional regulation of BMP4 synexpression in transgenic Xenopus. EMBO J. 2004;23:844-856.
41. Herrera B, Inman GJ. A rapid and sensitive bioassay for the simultaneous measurement of multiple bone morphogenetic proteins. Identification and quantification of BMP4, BMP6 and BMP9 in bovine and human serum. BMC Cell Biol. 2009;10:20.
42. Lin C, Zhao X, Sun D, et al. Transcriptional activation of follistatin by Nrf2 protects pulmonary epithelial cells against silica nanoparticle-induced oxidative stress. Sci Rep. 2015;6:21133.
43. Silva-Gomes S, Santos AG, Caldas C, et al. Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death. J Hepatol. 2014;60:354-361.
44. Nagarajan RP, Zhang J, Li W, et al. Regulation of Smad7 promoter by direct association with Smad3 and Smad4. J Biol Chem. 1999;274:33412-33418.
45. von Gersdorff G, Susztak K, Rezvani F, et al. Smad3 and Smad4 mediate transcriptional activation of the human Smad7 promoter by transforming growth factor beta. J Biol Chem. 2000;275:11320-11326.