title: Dietary phosphate restriction suppresses phosphaturia but does not prevent FGF23 elevation in a mouse model of chronic kidney disease.
abstract: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that in end-stage renal disease is markedly increased in serum; however, the mechanisms responsible for this increase are unclear. Here, we tested whether phosphate retention in chronic kidney disease (CKD) is responsible for the elevation of FGF23 in serum using Col4α3 knockout mice, a murine model of Alport disease exhibiting CKD. We found a significant elevation in serum FGF23 in progressively azotemic 8- and 12-week-old CKD mice along with an increased fractional excretion of phosphorus. Both moderate and severe phosphate restriction reduced fractional excretion of phosphorus by 8 weeks, yet serum FGF23 levels remained strikingly elevated. By 12 weeks, FGF23 levels were further increased with moderate phosphate restriction, while severe phosphate restriction led to severe bone mineralization defects and decreased FGF23 production in bone. CKD mice on a control diet had low serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D) levels and 3-fold higher renal Cyp24α1 gene expression compared to wild-type mice. Severe phosphate restriction increased 1,25(OH)(2)D levels in CKD mice by 8 weeks and lowered renal Cyp24α1 gene expression despite persistently elevated serum FGF23. Renal klotho gene expression declined in CKD mice on a control diet, but improved with severe phosphate restriction. Thus, dietary phosphate restriction reduces the fractional excretion of phosphorus independent of serum FGF23 levels in mice with CKD.
authors.affiliation: The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Shiqin
authors.initials: S
authors.lastname: Zhang
authors.forename: Ryan
authors.initials: R
authors.lastname: Gillihan
authors.forename: Nan
authors.initials: N
authors.lastname: He
authors.forename: Timothy
authors.initials: T
authors.lastname: Fields
authors.forename: Shiguang
authors.initials: S
authors.lastname: Liu
authors.forename: Troy
authors.initials: T
authors.lastname: Green
authors.forename: Jason R
authors.initials: JR
authors.lastname: Stubbs
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D024141:Collagen Type IV / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism; D007015:Hypophosphatemia, Familial / Q000378:metabolism* / Q000517:prevention & control*; D007668:Kidney / Q000378:metabolism; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000378:metabolism*; D010710:Phosphates / Q000008:administration & dosage* / Q000172:deficiency* / Q000652:urine; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; C000717428:Fgf23 protein, mouse; D010710:Phosphates; C057112:type IV collagen alpha3 chain; D014807:Vitamin D; D005346:Fibroblast Growth Factors; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D005966:Glucuronidase; D000090265:Klotho Proteins