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International Journal of Hematology

, Volume 109, Issue 1, pp 59–69 | Cite as

Deregulated iron metabolism in bone marrow from adenine-induced mouse model of chronic kidney disease

  • Tomoko Kimura
  • Takahiro KuraganoEmail author
  • Kiyoko Yamamoto
  • Masayoshi Nanami
  • Yukiko Hasuike
  • Takeshi Nakanishi
Original Article
  • 167 Downloads

Abstract

Although the primary cause of anemia in chronic kidney disease (CKD) is lack of sufficient erythropoietin (EPO), other factors may be involved, including the deregulation of iron metabolism. To clarify the mechanism of deranged erythropoiesis in CKD, we evaluated bone marrow (BM) cells in adenine-induced CKD mice. They showed even higher EPO expression in the kidney. Hepatic hepcidin mRNA and plasma hepcidin and ferritin levels were increased. Flow cytometry revealed a decrease in the number of cells expressing transferrin receptor (TfR), or late erythroid progenitors in BM; these cells correspond to proerythroblasts, and basophilic and polychromatic erythroblasts. In CKD mice, levels of erythroferrone mRNA in BM and splenic cells were significantly decreased, and MafB protein levels in BM cells were significantly increased. These results suggest that, in BM, the decrease in TfR, which may be associated with increased MafB levels, and the decrease in erythroferrone increase hepatic hepcidin expression, which may perturb iron recycling and erythropoiesis.

Keywords

TfR Hepcidin MafB Renal anemia CKD 

Notes

Acknowledgements

We gratefully acknowledge the efforts and contributions of this study. We thank Dr. Takanori Nagai, Miss. Ayako Goto, and Mrs. Eiko Akabane.

Authors’ contributions

TK, TK, RL and TN designed the trial. TK and KY performed the animal study. TK and TH measured the parameters. MN and YH performed the statistical analyses. All authors contributed to the data analysis and wrote the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

None declared.

References

  1. 1.
    Fisher JW. Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood). 2003;228:1–14.CrossRefGoogle Scholar
  2. 2.
    Nakhoul G, Simon JF. Anemia of chronic kidney disease; treat it, but not too aggressively. Cleve Clin J Med. 2016;83:613–24.CrossRefGoogle Scholar
  3. 3.
    Radtke HW, Claussner A, Erbes PM, Scheuermann EH, Schoeppe W, Koch KM. Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood. 1979;54:877–84.Google Scholar
  4. 4.
    Fukushima Y, Fukuda M, Yoshida K, Yamaguchi A, Nakamoto Y, Miura AB, et al. Serum Erythropoietin levels and inhibitors of erythropoiesis in patients with chronic renal failure. Tohoku J Exp Med. 1986;150:1–15.CrossRefGoogle Scholar
  5. 5.
    Macdougall IC. Role of uremic toxins in exacerbating anemia in renal failure. Kidney Int Suppl. 2001;78:67–72.CrossRefGoogle Scholar
  6. 6.
    Sun CC, Vaja V, Chen S, Theurl I, Stepanek A, Brown DE, et al. A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats. Nephrol Dial Transpl. 2013;28:1733–43.CrossRefGoogle Scholar
  7. 7.
    Jankowska EA, Kasztura M, Sokolski M, Bronisz M, Nawrocka S, Oleśkowska-Florek W, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. Eur Heart J. 2014;35:2468–76.CrossRefGoogle Scholar
  8. 8.
    Akchurin O, Sureshbabu A, Doty SB, Zhu YS, Patino E, Cunningham-Rundles S, et al. Lack of hepcidin ameliorates anemia and improves growth in an adenine-induced mouse model of chronic kidney disease. Am J Physiol Renal Physiol. 2016;311:F877–89.CrossRefGoogle Scholar
  9. 9.
    Khorramian E, Fung E, Chua K, Gabayan V, Ganz T, Nemeth E, et al. In a mouse model of sepsis, hepcidin ablation ameliorates anemia more effectively than iron and erythropoietin treatment. Shock. 2017;48:490–7.CrossRefGoogle Scholar
  10. 10.
    Koury MJ, Ponka P. New insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annu Rev Nutr. 2004;24:105–31.CrossRefGoogle Scholar
  11. 11.
    Williams KN, Szilagyi A, Conrad P, Halerz M, Kini AR, Li Y, et al. Peripheral blood mononuclear cell-derived erythroid progenitors and erythroblasts are decreased in burn patients. J Burn Care Res. 2013;34:133–41.CrossRefGoogle Scholar
  12. 12.
    Wang PW, Eisenbart JD, Cordes SP, Barsh GS, Stoffel M, Le Beau MM. Human KRML (MAFB): cDNA cloning, genomic structure, and evaluation as a candidate tumor suppressor gene in myeloid leukemias. Genomics. 1999;59:275–81.CrossRefGoogle Scholar
  13. 13.
    Sieweke MH, Tekotte H, Frampton J, Graf T. MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation. Cell. 1996;85:49–60.CrossRefGoogle Scholar
  14. 14.
    Kelly LM, Englmeier U, Lafon I, Sieweke MH, Graf T. MafB is an inducer of monocytic differentiation. EMBO J. 2000;19:1987–97.CrossRefGoogle Scholar
  15. 15.
    Hasan S, Johnson NB, Mosier MJ, Shankar R, Conrad P, Szilagyi A, et al. Myelo-erythroid commitment after burn injury is under beta-adrenergic control via MafB regulation. Am J Physiol Cell Physiol. 2017;312:C286–301.CrossRefGoogle Scholar
  16. 16.
    Jia T, Olauson H, Lindberg K, Amin R, Edvardsson K, Lindholm B, et al. A novel model of adenine-induced tubulointerstitial nephropathy in mice. BMC Nephrol. 2013;30:14:116.Google Scholar
  17. 17.
    Wong YT, Gruber J, Jenner AM, Ng MP, Ruan R, Tay FE. Elevation of oxidative-damage biomarkers during aging in F2 hybrid mice: protection by chronic oral intake of resveratrol. Free Radic Biol Med. 2009;46:799–809.CrossRefGoogle Scholar
  18. 18.
    Cao YA, Kusy S, Luong R, Wong RJ, Stevenson DK, Contag CH. Heme oxygenase-1 deletion affects stress erythropoiesis. PLoS One. 2011;6:e20634.CrossRefGoogle Scholar
  19. 19.
    Diwan A, Koesters AG, Odley AM, Pushkaran S, Baines CP, Spike BT, et al. Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc Natl Acad Sci U S A. 2007;104:6794–9.CrossRefGoogle Scholar
  20. 20.
    Liu J, Zhang J, Ginzburg Y, Li H, Xue F, De Franceschi L, et al. Quantitative analysis of murine terminal erythroid differentiation in vivo: novel method to study normal and disordered erythropoiesis. Blood. 2013;121:e43–9.CrossRefGoogle Scholar
  21. 21.
    Matusuo-Tezuka Y, Noguchi-Sasaki M, Kurasawa M, Yorozu K, Shimonaka Y. Quantitative analysis of dietary iron utilization for erythropoiesis in response to body iron status. Exp Hematol. 2016;44:491–501.CrossRefGoogle Scholar
  22. 22.
    Liu Y, Pop R, Sadegh C, Brugnara C, Haase VH, Socolovsky M. Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo. Blood. 2006;108:123–33.CrossRefGoogle Scholar
  23. 23.
    Elliott S, Pham E, Macdougall IC. Erythropoietins: a common mechanism of action. Exp Hematol. 2008;36:1573–84.CrossRefGoogle Scholar
  24. 24.
    Garrido P, Ribeiro S, Fernandes J, Vala H, Bronze-da-Rocha E, Belo L, et al. Iron-hepcidin dysmetabolism, anemia and renal hypoxia, inflammation and fibrosis in the remnant kidney rat model. PLoS One. 2015;10:e0124048.CrossRefGoogle Scholar
  25. 25.
    Jelkmann W. Regulation of erythropoietin production. J Physiol. 2011;589:1251–8.CrossRefGoogle Scholar
  26. 26.
    Gross AW, Lodish HF. Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem. 2006;281:2024–32.CrossRefGoogle Scholar
  27. 27.
    Hertzberg-Bigelman E, Barashi R, Levy R, Cohen L, Ben-Shoshan J, Keren G, et al. Down-regulation of cardiac erythropoietin receptor and its downstream activated signal transducer phospho-STAT-5 in a rat model of chronic kidney disease. Isr Med Assoc J. 2016;18:326–30.Google Scholar
  28. 28.
    Zeigler BM, Vajdos J, Qin W, Loverro L, Niss K. A mouse model for an erythropoietin-deficiency anemia. Dis Model Mech. 2010;3:763–72.CrossRefGoogle Scholar
  29. 29.
    Kautz L, Nemeth E. Molecular liaisons between erythropoiesis and iron metabolism. Blood. 2014;124:479–82.CrossRefGoogle Scholar
  30. 30.
    Harigae H. Iron metabolism and related diseases: an overview. Int J Hematol. 2018 Jan;107(1):5–6. doi.CrossRefGoogle Scholar
  31. 31.
    Papanikolaou G, Pantopoulos K. Systemic iron homeostasis and erythropoiesis. IUBMB Life. 2017;6 9:399–413.CrossRefGoogle Scholar
  32. 32.
    Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46:678–84.CrossRefGoogle Scholar
  33. 33.
    Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090–3.CrossRefGoogle Scholar
  34. 34.
    Keel SB, Doty R, Liu L, Nemeth E, Cherian S, Ganz T, et al. Evidence that the expression of transferrin receptor 1 on erythroid marrow cells mediates hepcidin suppression in the liver. Exp Hematol. 2015;43:469–78.CrossRefGoogle Scholar
  35. 35.
    Sieweke MH, Tekotte H, Frampton J, Graf T. MafB represses erythroid genes and differentiation through direct interaction with c-Ets-1. Leukemia. 1997; Suppl3 : 486–8.Google Scholar
  36. 36.
    Johnson NB, Posluszny JA, He LK, Szilagyi A, Gamelli G, Shankar RL, et al. Perturbed MafB/GATA1 axis after burn trauma bares the potential mechanism for immune suppression and anemia of critical illness. J Leukoc Biol. 2016;100:725–36.CrossRefGoogle Scholar
  37. 37.
    Zhang Y, Chen Q, Ross AC. Retinoic acid and tumor necrosis factor-α induced monocytic cell gene expression is regulated in part by induction of transcription factor MafB. Exp Cell Res. 2012;318:2407–16.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Tomoko Kimura
    • 1
  • Takahiro Kuragano
    • 1
    Email author
  • Kiyoko Yamamoto
    • 1
  • Masayoshi Nanami
    • 1
  • Yukiko Hasuike
    • 1
  • Takeshi Nakanishi
    • 1
  1. 1.Division of Kidney and Dialysis, Department of Internal MedicineHyogo College of MedicineNishinomiyaJapan

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