title: The phosphate transporter NaPi-IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels.
abstract: Renal reabsorption of inorganic phosphate (Pi) is mediated by the phosphate transporters NaPi-IIa, NaPi-IIc, and Pit-2 in the proximal tubule brush border membrane (BBM). Dietary Pi intake regulates these transporters; however, the contribution of the specific isoforms to the rapid and slow phase is not fully clarified. Moreover, the regulation of PTH and FGF23, two major phosphaturic hormones, during the adaptive phase has not been correlated. C57/BL6 and NaPi-IIa(-/-) mice received 5 days either 1.2 % (HPD) or 0.1 % (LPD) Pi-containing diets. Thereafter, some mice were acutely switched to LPD or HPD. Plasma Pi concentrations were similar under chronic diets, but lower when mice were acutely switched to LPD. Urinary Pi excretion was similar in C57/BL6 and NaPi-IIa(-/-) mice under HPD. During chronic LPD, NaPi-IIa(-/-) mice lost phosphate in urine compensated by higher intestinal Pi absorption. During the acute HPD-to-LPD switch, NaPi-IIa(-/-) mice exhibited a delayed decrease in urinary Pi excretion. PTH was acutely regulated by low dietary Pi intake. FGF23 did not respond to low Pi intake within 8 h whereas the phospho-adaptator protein FRS2α necessary for FGF-receptor cell signaling was downregulated. BBM Pi transport activity and NaPi-IIa but not NaPi-IIc and Pit-2 abundance acutely adapted to diets in C57/BL6 mice. In NaPi-IIa(-/-), Pi transport activity was low and did not adapt. Thus, NaPi-IIa mediates the fast adaptation to Pi intake and is upregulated during the adaptation to low Pi despite persistently high FGF23 levels. The sensitivity to FGF23 may be regulated by adapting FRS2α abundance and phosphorylation.
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zürich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
authors.forename: Soline
authors.initials: S
authors.lastname: Bourgeois
authors.forename: Paola
authors.initials: P
authors.lastname: Capuano
authors.forename: Gerti
authors.initials: G
authors.lastname: Stange
authors.forename: Reto
authors.initials: R
authors.lastname: Mühlemann
authors.forename: Heini
authors.initials: H
authors.lastname: Murer
authors.forename: Jürg
authors.initials: J
authors.lastname: Biber
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D000222:Adaptation, Physiological; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D007408:Intestinal Absorption; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016226:Phosphorus, Dietary / Q000097:blood / Q000378:metabolism* / Q000652:urine; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000717427:FGF23 protein, human; C488187:FRS2alpha protein, mouse; C000717428:Fgf23 protein, mouse; D008565:Membrane Proteins; D016226:Phosphorus, Dietary; C493555:Slc34a1 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23