Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients.
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.
Komaba
Hirotaka
H
Division of Nephrology and Kidney Center, Kobe University School of Medicine, Kobe, Japan. fukagawa@tokai-u.jp
Goto
Shunsuke
S
Fujii
Hideki
H
Hamada
Yasuhiro
Y
Kobayashi
Akira
A
Shibuya
Koji
K
Tominaga
Yoshihiro
Y
Otsuki
Naoki
N
Nibu
Ken-Ichi
K
Nakagawa
Kimie
K
Tsugawa
Naoko
N
Okano
Toshio
T
Kitazawa
Riko
R
Fukagawa
Masafumi
M
Kita
Tomoyuki
T
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*
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