In vivo evidence for a limited role of proximal tubular Klotho in renal phosphate handling.
Klotho is a transmembrane protein expressed in the renal tubules where it acts as a permissive coreceptor for fibroblast growth factor 23 (FGF23). FGF23 signaling reduces the abundance of CYP27b1 and phosphate cotransporters NPT2a and NPT2c, leading to a decrease in 1,25(OH)2D3 synthesis and a rise in urinary phosphate excretion, respectively. Systemic or whole-nephron deletion of Klotho in mice results in renal FGF23 resistance characterized by high 1,25(OH)2D3 and phosphate levels and premature aging. Expression of Klotho is highest in the distal tubules, whereas 25OH vitamin D 1α hydroxylation and phosphate reabsorption predominantly occur in the proximal tubules. Currently, the segment-specific roles of Klotho in renal tubules are not fully understood. Here we have generated mice with Klotho specifically ablated from the proximal tubules using 3 different Cre mouse strains. All 3 models displayed impaired urinary phosphate excretion and increased abundance of NPT2a in the brush border membrane. Notably, hyperphosphatemia in knockout mice was mild or nonexistent under basal conditions but occurred upon high phosphate loading, indicating the presence of compensatory mechanisms. Effects on 1,25(OH)2D3 varied between mouse strains but were modest overall. Thus, Klotho expressed in the proximal tubules has a defined but limited role in renal phosphate handling in vivo.
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Noriko
N
Ide
Division of Renal Medicine, Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
Hannes
H
Olauson
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Tadatoshi
T
Sato
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Michael Joseph
MJ
Densmore
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Hao
H
Wang
Division of Nephrology, Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Jun-Ichi
JI
Hanai
Division of Renal Medicine, Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
Tobias E
TE
Larsson
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, Massachusetts, USA. Electronic address: beate_lanske@hsdm.harvard.edu.
Beate
B
Lanske
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D019588:Aging, Premature / Q000378:metabolism; D000818:Animals; D002117:Calcitriol / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D054559:Hyperphosphatemia / Q000097:blood / Q000235:genetics; D007150:Immunohistochemistry; D007684:Kidney Tubules / Q000166:cytology / Q000502:physiology*; D000090265:Klotho Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D010710:Phosphates / Q000378:metabolism* / Q000652:urine; D061251:Primary Cell Culture; D065667:Renal Elimination; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000378:metabolism
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; C493555:Slc34a1 protein, mouse; C493563:Slc34a3 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol
1,25(OH)(2)D(3); Cre/loxP; Fgf23; Npt2a; mineral metabolism