Xeno-Klotho Inhibits Parathyroid Hormone Signaling.
Although fibroblast growth factor (FGF) 23 was recently identified as a phosphatonin that influences vitamin D metabolism, the underlying signaling mechanisms remain unclear. FGF23 elevates the renal levels of membrane-associated klotho as well as soluble klotho. Klotho is expressed on distal tubules. Upon enzymatic cleavage, soluble klotho is released into the renal interstitial space and then into the systemic circulation. The expression of 25-hydroxyvitamin D3 1α-hydroxylase (1-OH) on proximal tubular cells is controlled by parathyroid hormone (PTH). Klotho binds to various membrane proteins to alter their function. Here, the interaction between the PTH receptor and klotho was studied using various approaches, including immunoprecipitation, in vitro cell culture, and in vivo animal experiments. Immunoprecipitation studies demonstrate, for the first time, that recombinant human klotho protein interacts with human PTH receptors to inhibit the binding of human PTH. Furthermore, when applied to human proximal tubular cells, recombinant human klotho suppresses PTH-stimulated generation of inositol trisphosphate in vitro. Moreover, PTH-induced increase of cyclic AMP secretion and 1α,25-dihydroxyvitamin D3 (1,25VD) was attenuated by recombinant human klotho in vivo. In addition, recombinant human klotho inhibits the expression of 1-OH by PTH both in vitro and in vivo. These results suggest that free klotho mediates the FGF23-induced inhibition of 1,25VD synthesis.
Department of Medicine, International University of Health and Welfare, Clinical Research Center, Sanno Hospital, Tokyo, Japan.
Tsuneo
T
Takenaka
Department of Nephrology, Saitama Medical University, Saitama, Japan.
Tsutomu
T
Inoue
Community Health Science Center, Saitama Medical University, Saitama, Japan.
Takashi
T
Miyazaki
Dialysis and Blood Purification Center, Keio University, Tokyo, Japan.
Matsuhiko
M
Hayashi
Department of Nephrology, Saitama Medical University, Saitama, Japan.
Hiromichi
H
Suzuki
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D002117:Calcitriol / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D000090265:Klotho Proteins; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C000717427:FGF23 protein, human; D010281:Parathyroid Hormone; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol
CALCIUM; FGF23; KLOTHO; PARATHYROID; PHOSPHATE; VITAMIN D