Parathyroid Klotho and FGF-receptor 1 expression decline with renal function in hyperparathyroid patients with chronic kidney disease and kidney transplant recipients.
Current studies suggest that short-term exposure of parathyroid glands to fibroblast growth factor 23 (FGF23) reduces parathyroid hormone secretion. However, patients with chronic kidney disease (CKD) develop secondary hyperparathyroidism despite high levels of serum FGF23, indicating a parathyroid FGF23 'resistance'. Here we analyzed the expression of the FGF23 receptors Klotho and FGF receptor 1 (FGFR1) in 88 hyperplastic parathyroid glands from 31 patients with CKD (including 21 renal allograft recipients), and their regulation in isolated bovine and human hyperplastic parathyroid cells. Glandular expression was variable, yet the Klotho and FGFR1 mRNA levels declined in parallel with the decreasing glomerular filtration rate, significantly decreasing over CKD stages. We found no association between the expression of Klotho, FGFR1, and the proliferation marker Ki67. In vitro treatment of bovine cells with FGF23 or calcium reduced the Klotho level, whereas active vitamin D(3) compounds increased its expression. Phosphate and parathyroid hormone had no effect. Treatment had less impact on Klotho in cultured human cells than in the bovine healthy cell model, whereas FGFR1 expression was induced in the hyperplastic cells. Thus parathyroid Klotho and FGFR1 decrease with declining renal function, possibly because of alterations in mineral metabolism related to the failing kidney. This could explain the observed parathyroid resistance to FGF23 in late CKD.
Krajisnik
Tijana
T
Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Tijana.Krajisnik@medsci.uu.se
Olauson
Hannes
H
Mirza
Majd A I
MA
Hellman
Per
P
Akerström
Göran
G
Westin
Gunnar
G
Larsson
Tobias E
TE
Björklund
Peyman
P
D000328:Adult; D000368:Aged; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D006961:Hyperparathyroidism / Q000378:metabolism* / Q000473:pathology; D006965:Hyperplasia / Q000473:pathology; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D016030:Kidney Transplantation / Q000502:physiology*; D000090265:Klotho Proteins; D008297:Male; D008875:Middle Aged; D008903:Minerals / Q000378:metabolism; D010280:Parathyroid Glands / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010281:Parathyroid Hormone / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D012189:Retrospective Studies
C000717427:FGF23 protein, human; D008903:Minerals; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins