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Deletion of Xenotropic and Polytropic Retrovirus Receptor 1 in mouse nephron causes renal Fanconi syndrome and hypophosphatemic rickets
Author(s) -
Ansermet Camille,
Moor Matthias,
Centeno Gabriel,
Auberson Muriel,
Hu Dorothy,
Barron Roland,
Nikolaeva Svetlana,
Haenzi Barbara,
Katanaeva Natalya,
Gautschi Ivan,
Katanaev Vladimir,
Rotman Samuel,
Koesters Robert,
Schild Laurent,
Pradervand Sylvain,
Bonny Olivier,
Firsov Dmitri
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.857.9
Subject(s) - hypophosphatemia , hypophosphatemic rickets , endocrinology , medicine , reabsorption , fanconi syndrome , osteomalacia , chemistry , nephron , rickets , phex , kidney , renal tubular acidosis , biology , osteoporosis , vitamin d and neurology , acidosis
Phosphate (Pi) is one of the most abundant minerals in the body and tight control of extra‐ and intracellular Pi concentrations is crucial for many biological processes. The kidney is the main organ involved in the regulation of minute‐to‐minute phosphate homeostasis by controlling Pi reabsorption from the primary urine. This reabsorption primarily occurs in the proximal tubule by the action of the apical sodium‐dependent phosphate transporters NaPi‐IIa, NaPi‐IIc and PiT2. The protein(s) involved in the basolateral phosphate efflux remain unknown. As recent in vitro and genetic studies have linked the xenotropic and polytropic receptor 1 (Xpr1) to Pi efflux, we aimed to assess if it could also be involved in renal Pi reabsorption. To address this question, we used the Pax8‐rtTA‐driven Cre expression system, allowing a conditional inactivation of Xpr1 in mouse renal tubule. Functional analysis showed that conditional Xpr1 knockout mice (cKO) have hypophosphatemia with transient hyperphosphaturia, an increase in fractional excretion of phosphate (FEPi) along with a decreased TmPi/GFR. These phosphate disturbances leaded us to study the bone phenotype. Micro‐CT analysis of vertebrae revealed significant decrease in bone mineral density, percent bone volume and trabecular thickness and number in male cKO mice, characteristic of osteoporosis and osteomalacia. Histomorphometric analysis of vertebrae also showed an increase in unmineralized osteoid and osteoclastogenesis in cKO mice. Moreover, ex‐vivo experiments using primary cultures of proximal tubule of Control and cKO mice showed that Xpr1 deficiency strongly affects the [ 33 P]phosphate efflux whereas the [ 33 P]phosphate uptake remains similar between Control and cKO cells. Additional phenotypic observations in cKO mice include aminoaciduria, glycosuria, hypercalcuria, hypercalcemia and proteinuria, indicating that these mice are developing a complete Fanconi syndrome, a generalized proximal tubular dysfunction. Taken together, these results support a significant role for Xpr1 in renal phosphate homeostasis. Support or Funding Information This work was supported by the Swiss National Science Foundation Research grants 31003A‐149440 and 310030‐163340