title: Genetic knockout and pharmacologic inhibition of NCX2 cause natriuresis and hypercalciuria.
abstract: The Na(+)/Ca(2+) exchanger (NCX) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na(+) and Ca(2+). Although two isoforms of NCX1 and NCX2 are coexpressed on the basolateral membrane of the distal nephron, the functional significance of these isoforms is not entirely clear. Therefore, we used NCX1- and NCX2-heterozygote knockout mice (KO) and their double KO, as well as isoform-selective NCX inhibitors, to determine the roles of NCX isoforms in urine formation and electrolyte excretion in mice. NCX inhibitors, particularly NCX2-sensitive inhibitors, caused a dose-dependent natriuresis and in a higher dose, moreover, hypercalciuria. Consistently, NCX1-KO possessed normal renal function similar to wild-type mice (WT), whereas NCX2-KO and double KO exhibited moderate natriuresis and hypercalciuria. Notably, renal responses to YM-244769 were equivalently observed in NCX1-KO and WT, but disappeared in NCX2-KO and double KO. Thus, functional inhibition of NCX2 initially causes natriuresis, and further inhibition of NCX2 produces hypercalciuria, suggesting that the functional significance of NCX2 lies in Na(+) and Ca(2+) reabsorption of the kidney.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Gotoh
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Kita
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Horie
authors.affiliation: Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan. Electronic address: tiwamoto@fukuoka-u.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwamoto
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D055786:Gene Knockout Techniques; D053565:Hypercalciuria / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009318:Natriuresis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010647:Phenyl Ethers / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000814:Aniline Compounds; C516554:N-(3-aminobenzyl)-6-(4-((3-fluorobenzyl)oxy)phenoxy)nicotinamide; D010647:Phenyl Ethers; D020033:Protein Isoforms; C430918:SEA 0400; C491739:Slc8a2 protein, mouse; D019831:Sodium-Calcium Exchanger; D009536:Niacinamide; D013890:Thiourea
keywords: Genetic knockout; Hypercalciuria; NCX inhibitors; NCX isoforms; Natriuresis