Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Fisher JW. Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood). 2003;228:1–14.

    Article  CAS  Google Scholar 

  2. Nakhoul G, Simon JF. Anemia of chronic kidney disease; treat it, but not too aggressively. Cleve Clin J Med. 2016;83:613–24.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  5. Macdougall IC. Role of uremic toxins in exacerbating anemia in renal failure. Kidney Int Suppl. 2001;78:67–72.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Koury MJ, Ponka P. New insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annu Rev Nutr. 2004;24:105–31.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  14. Kelly LM, Englmeier U, Lafon I, Sieweke MH, Graf T. MafB is an inducer of monocytic differentiation. EMBO J. 2000;19:1987–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Elliott S, Pham E, Macdougall IC. Erythropoietins: a common mechanism of action. Exp Hematol. 2008;36:1573–84.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jelkmann W. Regulation of erythropoietin production. J Physiol. 2011;589:1251–8.

    Article  CAS  PubMed  Google Scholar 

  26. Gross AW, Lodish HF. Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem. 2006;281:2024–32.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  29. Kautz L, Nemeth E. Molecular liaisons between erythropoiesis and iron metabolism. Blood. 2014;124:479–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Harigae H. Iron metabolism and related diseases: an overview. Int J Hematol. 2018 Jan;107(1):5–6. doi.

    Article  CAS  PubMed  Google Scholar 

  31. Papanikolaou G, Pantopoulos K. Systemic iron homeostasis and erythropoiesis. IUBMB Life. 2017;6 9:399–413.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. Division of Kidney and Dialysis, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    Tomoko Kimura, Takahiro Kuragano, Kiyoko Yamamoto, Masayoshi Nanami, Yukiko Hasuike & Takeshi Nakanishi

Authors
  1. Tomoko Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takahiro Kuragano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kiyoko Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masayoshi Nanami
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yukiko Hasuike
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takeshi Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Takahiro Kuragano.

Ethics declarations

Conflict of interest

None declared.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kimura, T., Kuragano, T., Yamamoto, K. et al. Deregulated iron metabolism in bone marrow from adenine-induced mouse model of chronic kidney disease. Int J Hematol 109, 59–69 (2019). https://doi.org/10.1007/s12185-018-2531-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-018-2531-2

Keywords

Search

Navigation