Na+/H+ exchanger 3 inhibitor diminishes hepcidin-enhanced duodenal calcium transport in hemizygous β-globin knockout thalassemic mice
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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.
KeywordsBeta-thalassemia Calcium absorption Hepcidin Tenapanor Ussing chamber
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.
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.
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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