title: Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients.
abstract: Fibroblast growth factor 23 (FGF23) exerts its effect by binding to its cognate FGF receptor 1 (FGFR1) in the presence of its co-receptor Klotho. Parathyroid glands express both FGFR1 and Klotho, and FGF23 decreases parathyroid hormone gene expression and hormone secretion directly. In uremic patients with secondary hyperparathyroidism (SHPT), however, parathyroid hormone secretion remains elevated despite extremely high FGF23 levels. To determine the mechanism of this resistance, we measured the expression of Klotho, FGFR1, and the proliferative marker Ki67 in 7 normal and 80 hyperplastic parathyroid glands from uremic patients by immunohistochemistry. All uremic patients had severe SHPT along with markedly high FGF23 levels. Quantitative real-time reverse transcription PCR showed that the mRNA levels for Klotho and FGFR1correlated significantly with their semi-quantitative immunohistochemical intensity. Compared with normal tissue, the immunohistochemical expression of Klotho and FGFR1 decreased, but Ki67 expression increased significantly in hyperplastic parathyroid glands, particularly in glands with nodular hyperplasia. These results suggest that the depressed expression of the Klotho-FGFR1 complex in hyperplastic glands underlies the pathogenesis of SHPT and its resistance to extremely high FGF23 levels in uremic patients.
authors.affiliation: Division of Nephrology and Kidney Center, Kobe University School of Medicine, Kobe, Japan. fukagawa@tokai-u.jp
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Komaba
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Goto
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hamada
authors.forename: Akira
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Koji
authors.initials: K
authors.lastname: Shibuya
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tominaga
authors.forename: Naoki
authors.initials: N
authors.lastname: Otsuki
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Nibu
authors.forename: Kimie
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsugawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Okano
authors.forename: Riko
authors.initials: R
authors.lastname: Kitazawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kita
mesh_terms: D016022:Case-Control Studies; D015536:Down-Regulation; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000032:analysis; D005966:Glucuronidase / Q000235:genetics*; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000209:etiology*; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D000090265:Klotho Proteins; D010280:Parathyroid Glands / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D014511:Uremia / Q000150:complications*
chemical_list: C000717427:FGF23 protein, human; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005966:Glucuronidase; D000090265:Klotho Proteins