Molecular and Cellular Biochemistry

, Volume 427, Issue 1–2, pp 201–208 | Cite as

Na+/H+ exchanger 3 inhibitor diminishes hepcidin-enhanced duodenal calcium transport in hemizygous β-globin knockout thalassemic mice

  • Narattaphol Charoenphandhu
  • Kamonshanok Kraidith
  • Kornkamon Lertsuwan
  • Chanakarn Sripong
  • Panan Suntornsaratoon
  • Saovaros Svasti
  • Nateetip Krishnamra
  • Kannikar Wongdee
Article

Abstract

Recent investigation has shown that the liver-derived iron-regulating hormone, hepcidin, can potentiate intestinal calcium absorption in hemizygous β-globin knockout thalassemic (BKO) mice. Since the upregulation of Fe2+ and H+ cotransporter, divalent metal transporter (DMT)-1, has been shown to correlate with thalassemia-induced intestinal calcium absorption impairment, the inhibition of the apical Na+/H+ exchanger (NHE)-3 that is essential for cytoplasmic pH regulation and transepithelial sodium absorption was hypothesized to negatively affect hepcidin action. Herein, the positive effect of hepcidin on the duodenal calcium transport was evaluated using Ussing chamber technique. The results showed that BKO mice had lower absorptive surface area and duodenal calcium transport than wild-type mice. Besides, paracellular transport of zinc in BKO mice was compromised. Hepcidin administration completely restored calcium transport. Since this hepcidin action was totally abolished by inhibitors of the basolateral calcium transporters, Na+/Ca2+ exchanger (NCX1) and plasma membrane Ca2+-ATPase (PMCA1b), the enhanced calcium flux potentially occurred through the transcellular pathway rather than paracellular pathway. Interestingly, the selective NHE3 inhibitor, 100 nM tenapanor, markedly inhibited hepcidin-enhanced calcium transport. Accordingly, hepcidin is one of the promising therapeutic agents for calcium malabsorption in β-thalassemia. It mainly stimulates the transcellular calcium transport across the duodenal epithelium in an NHE3-dependent manner.

Keywords

Beta-thalassemia Calcium absorption Hepcidin Tenapanor Ussing chamber 

Notes

Author contribution

Conception and design of research—NC and KW. Performed experiments—NC, PS, KK, KL, CS, SS, and KW. Analyzed data—NC, PS, KK, KL, CS, SS, NK, and KW. Interpreted results of experiments—NC, PS, KK, KL, CS, SS, NK, and KW. Prepared figures—NC, PS, KK, CS, and KW. Drafted manuscript—NC, KL, SS, NK, and KW. Edited and revised manuscript—NC, KL, SS, NK, and KW. Approved final version of manuscript—NC, PS, KK, KL, CS, SS, NK, and KW.

Funding

This study was supported by the grants from Mahidol University (to NC), the Thailand Research Fund (TRF)–Mahidol University through the TRF Senior Research Scholar Grant (RTA5780001 to NC), the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (PHD/0219/2553, to KK), the Faculty of Science, Mahidol University (to NC), Office of the Higher Education Commission and Mahidol University under the National Research University Initiative (to SS), the Research Chair Grant, the National Science and Technology Development Agency (NSTDA; to SS), the Faculty of Allied Health Sciences, Burapha University and Thailand Research Fund through TRF Research Scholar Award (RSA5780041 to KW), the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission (185100 to KW). NC and KW are also supported by TRF International Research Network Program (IRN59W0002).

Compliance with ethical standards

Conflict of interests

The authors declare that they have no conflict of interests.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Narattaphol Charoenphandhu
    • 1
    • 2
    • 4
  • Kamonshanok Kraidith
    • 1
    • 2
  • Kornkamon Lertsuwan
    • 1
    • 3
  • Chanakarn Sripong
    • 1
    • 2
  • Panan Suntornsaratoon
    • 1
    • 2
  • Saovaros Svasti
    • 6
  • Nateetip Krishnamra
    • 1
    • 2
  • Kannikar Wongdee
    • 1
    • 5
  1. 1.Center of Calcium and Bone Research (COCAB), Faculty of ScienceMahidol UniversityBangkokThailand
  2. 2.Department of Physiology, Faculty of ScienceMahidol UniversityBangkokThailand
  3. 3.Department of Biochemistry, Faculty of ScienceMahidol UniversityBangkokThailand
  4. 4.Institute of Molecular BiosciencesMahidol UniversitySalayaThailand
  5. 5.Office of Academic Management, Faculty of Allied Health SciencesBurapha UniversityChonburiThailand
  6. 6.Thalassemia Research Center, Institute of Molecular BiosciencesMahidol UniversitySalayaThailand

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