title: Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice.
abstract: The proximal renal epithelia express three different Na-dependent inorganic phosphate (Pi) cotransporters: NaPi-IIa/SLC34A1, NaPi-IIc/SLC34A3, and PiT2/SLC20A2. Constitutive mouse knockout models of NaPi-IIa and NaPi-IIc suggested that NaPi-IIa mediates the bulk of renal reabsorption of Pi whereas the contribution of NaPi-IIc to this process is minor and probably restricted to young mice. However, many reports indicate that mutations of NaPi-IIc in humans lead to hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report the generation of a kidney-specific and inducible NaPi-IIc-deficient mouse model based on the loxP-Cre system. We found that the specific removal of the cotransporter from the kidneys of young mice does not impair the capacity of the renal epithelia to transport Pi. Moreover, the levels of Pi in plasma and urine as well as the circulating levels of parathyroid hormone, FGF-23, and vitamin D3 remained unchanged. These findings are in agreement with the data obtained with the constitutive knockout model and suggest that, under steady-state conditions of normal dietary Pi, NaPi-IIc is not an essential Na-Pi cotransporter in murine kidneys. However, and unlike the constitutive mutants, the kidney-specific depletion of NaPi-IIc does not result in alteration of the homeostasis of calcium. This suggests that the calcium-related phenotype observed in constitutive knockout mice may not be related to inactivation of the cotransporter in kidney.
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology. Univ. of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. hernando@physiol.uzh.ch.
authors.forename: Komuraiah
authors.initials: K
authors.lastname: Myakala
authors.forename: Sarah
authors.initials: S
authors.lastname: Motta
authors.forename: Heini
authors.initials: H
authors.lastname: Murer
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.forename: Robert
authors.initials: R
authors.lastname: Koesters
authors.forename: Jürg
authors.initials: J
authors.lastname: Biber
authors.forename: Nati
authors.initials: N
authors.lastname: Hernando
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D053098:Familial Hypophosphatemic Rickets / Q000503:physiopathology; D000089703:Fibroblast Growth Factor-23; D006706:Homeostasis / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010710:Phosphates / Q000378:metabolism*; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000172:deficiency / Q000235:genetics*
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; C493563:Slc34a3 protein, mouse; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D000089703:Fibroblast Growth Factor-23; D002117:Calcitriol; D004318:Doxycycline; D002118:Calcium
keywords: SLC34 cotransporters; epithelial transport; phosphate homeostasis; renal proximal tubules