title: Intestinal Depletion of NaPi-IIb/Slc34a2 in Mice: Renal and Hormonal Adaptation.
abstract: The Na(+) -dependent phosphate-cotransporter NaPi-IIb (SLC34A2) is widely expressed, with intestine, lung, and testis among the organs with highest levels of mRNA abundance. In mice, the intestinal expression of NaPi-IIb is restricted to the ileum, where the cotransporter localizes specifically at the brush border membrane (BBM) and mediates the active transport of inorganic phosphate (Pi). Constitutive full ablation of NaPi-IIb is embryonically lethal whereas the global but inducible removal of the transporter in young mice leads to intestinal loss of Pi and lung calcifications. Here we report the generation of a constitutive but intestinal-specific NaPi-IIb/Slc34a2-deficient mouse model. Constitutive intestinal ablation of NaPi-IIb results in viable pups with normal growth. Homozygous mice are characterized by fecal wasting of Pi and complete absence of Na/Pi cotransport activity in BBM vesicles (BBMVs) isolated from ileum. In contrast, the urinary excretion of Pi is reduced in these animals. The plasma levels of Pi are similar in wild-type and NaPi-IIb-deficient mice. In females, the reduced phosphaturia associates with higher expression of NaPi-IIa and higher Na/Pi cotransport activity in renal BBMVs, as well as with reduced plasma levels of intact FGF-23. A similar trend is found in males. Thus, NaPi-IIb is the only luminal Na(+) -dependent Pi transporter in the murine ileum and its absence is fully compensated for in adult females by a mechanism involving the bone-kidney axis. The contribution of this mechanism to the adaptive response is less apparent in adult males.
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP). University of Zurich, Zurich, Switzerland.
authors.forename: Nati
authors.initials: N
authors.lastname: Hernando
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP). University of Zurich, Zurich, Switzerland.
authors.forename: Komuraiah
authors.initials: K
authors.lastname: Myakala
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP). University of Zurich, Zurich, Switzerland.
authors.forename: Fabia
authors.initials: F
authors.lastname: Simona
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP). University of Zurich, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Knöpfel
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP). University of Zurich, Zurich, Switzerland.
authors.forename: Linto
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP). University of Zurich, Zurich, Switzerland.
authors.forename: Heini
authors.initials: H
authors.lastname: Murer
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP). University of Zurich, Zurich, Switzerland.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP). University of Zurich, Zurich, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Biber
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D007015:Hypophosphatemia, Familial / Q000378:metabolism; D007082:Ileum / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008871:Microvilli / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010710:Phosphates / Q000097:blood* / Q000652:urine*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000235:genetics / Q000378:metabolism*
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D012333:RNA, Messenger; C493558:Slc34a2 protein, mouse; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: FGF-23; PHOSPHATE HOMEOSTASIS; PTH; SLC34A1; VITAMIN D3