title: Na+/H+exchanger 3 inhibitor diminishes hepcidin-enhanced duodenal calcium transport in hemizygous β-globin knockout thalassemic mice.
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.
authors.affiliation: Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.|Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.|Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand.
authors.forename: Narattaphol
authors.initials: N
authors.lastname: Charoenphandhu
authors.affiliation: Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.|Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Kamonshanok
authors.initials: K
authors.lastname: Kraidith
authors.affiliation: Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.|Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Kornkamon
authors.initials: K
authors.lastname: Lertsuwan
authors.affiliation: Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.|Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Chanakarn
authors.initials: C
authors.lastname: Sripong
authors.affiliation: Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.|Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Panan
authors.initials: P
authors.lastname: Suntornsaratoon
authors.affiliation: Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand.
authors.forename: Saovaros
authors.initials: S
authors.lastname: Svasti
authors.affiliation: Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.|Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Nateetip
authors.initials: N
authors.lastname: Krishnamra
authors.affiliation: Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand. kannikar@go.buu.ac.th.|Office of Academic Management, Faculty of Allied Health Sciences, Burapha University, Chonburi, Thailand. kannikar@go.buu.ac.th.
authors.forename: Kannikar
authors.initials: K
authors.lastname: Wongdee
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism* / Q000473:pathology; D005260:Female; D064451:Hepcidins / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013789:Thalassemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism*
chemical_list: D064451:Hepcidins; D007546:Isoquinolines; C499849:NCX1 protein, mouse; C556012:Pmca1b protein, mouse; C000613386:Slc9a3 protein, mouse; D019831:Sodium-Calcium Exchanger; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D013449:Sulfonamides; D055544:beta-Globins; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium; C000599417:tenapanor
keywords: Beta-thalassemia; Calcium absorption; Hepcidin; Tenapanor; Ussing chamber