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Parathyroid Klotho Expression Declines with Renal Function in Hyperparathyroid CKD Patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. (Metabola Bensjukdomar, Fosfatmetabolism)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. (Metabola Bensjukdomar, Fosfatmetabolism)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. (Metabola Bensjukdomar, Fosfatmetabolism)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Current data suggest that type I membrane-bound α-Klotho plays a dual role in the regulation of PTH secretion. While stimulating PTH release during hypocalcemia, Klotho inhibits PTH production by mediating the suppressive effect of fibroblast growth factor-23 (FGF23). In chronic kidney disease (CKD), secondary hyperparathyroidism (sHPT) often develops in the presence of high serum FGF23, indicating parathyroid resistance to FGF23 action. This could in part be due to reduced Klotho expression, as reported in kidneys of CKD patients. Herein, we analyzed parathyroid Klotho expression level in 31 patients with sHPT as well as regulation of Klotho in isolated bovine parathyroid cells using real-time PCR analysis and IHC staining. Klotho expression was variable in secondary hyperplastic glands, yet the mRNA levels correlated positively with glomerular filtration rate and significantly decreased over CKD stages. In vitro treatment with either FGF23 or calcium dose-dependently reduced the Klotho level, whereas vitamin D treatment increased its expression. This stimulatory effect was blunted in the presence of either high FGF23 or calcium. No effect on Klotho level was observed after treatment with phosphate or PTH. In summary, parathyroid Klotho expression was variable in sHPT but decreased with declining renal function. This may be due to a complex co-regulation by calcium, FGF23 and vitamin D, and explain the lack of suppressive effects of FGF23 on PTH secretion in late CKD.

Keyword [en]
Klotho, CKD, chronic kidney disease, fibroblast growth factor-23, FGF23, phosphate, sHPT, secondary hyperparathyroidism, vitamin D
National Category
Endocrinology and Diabetes
Research subject
Internal Medicine
Identifiers
URN: urn:nbn:se:uu:diva-107450OAI: oai:DiVA.org:uu-107450DiVA: diva2:229415
Note
*These authors contributed equally.Available from: 2009-08-12 Created: 2009-08-12 Last updated: 2010-01-14
In thesis
1. Fibroblast growth factor-23 and Klotho in bone/mineral and parathyroid disorders
Open this publication in new window or tab >>Fibroblast growth factor-23 and Klotho in bone/mineral and parathyroid disorders
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fibroblast growth factor-23 (FGF23) is a novel, bone-produced hormone that regulates renal phosphate (Pi) reabsorption and calcitriol metabolism. Disorders of mineral and bone metabolism, such as autosomal dominant hypophosphatemic rickets (ADHR) and hyperostosis-hyperphosphatemia syndrome (HHS), witness the importance of well-balanced serum levels of FGF23. Patients with chronic kidney disease (CKD) are highly morbid due to Pi retention/hyperphosphatemia and calcitriol deficiency, which lead to elevated serum levels of parathyroid hormone (PTH) and secondary hyperparathyroidism (sHPT). As a response to hyperphosphatemia, CKD patients have also remarkably high serum FGF23 levels, which are associated with cardiovascular risk factors and increased mortality in CKD. The overall aim of this dissertation was to discern a possible role of FGF23 in parathyroid biology. Our in vitro experiments on isolated bovine parathyroid cells demonstrate that FGF23 directly and dose-dependently suppresses the PTH production and secretion, while increasing the expression of the 25-hydroxyvitamin D3-activating enzyme 1α-hydroxylase. We investigated possible expressional changes in the FGF23 receptor co-factor Klotho in hyperparathyroid disorders and found that Klotho expression is decreased or absent and inversely correlated to serum calcium (Ca) in adenomas of primary HPT (pHPT). In the hyperplastic parathyroid glands of sHPT, Klotho expression declines in parallel with the kidney function and correlates with the glomerular filtration rate. Moreover, Klotho expression is suppressed by Ca and FGF23, increased by calcitriol, but unaffected by Pi and PTH in vitro. Finally, we identified a novel missense mutation in the gene encoding GALNT3, which is normally involved in the post-translational glycosylation of FGF23, as the cause of aberrant FGF23 processing in a patient with HHS. In summary, we provide evidence for a novel bone/parathyroid axis in which FGF23 functions as a direct, negative regulator of the PTH production. High extracellular Ca is a major determinant of the Klotho expression in pHPT, whereas the Klotho levels in sHPT may be attributed to a combination of the high FGF23 and Ca, and low calcitriol levels associated with CKD. Hence, the decreased Klotho expression in sHPT could explain the concomitantly high FGF23 and PTH levels, as well as the failure of FGF23 to prevent or mitigate the development of sHPT in CKD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 475
Keyword
calcitriol, chronic kidney disease, CKD, chronic renal failure, fibroblast growth factor 23, fibroblast growth factor-23, FGF23, FGF-23, GalNac-T3, GALNT3, GFR, hyperostosis-hyperphosphatemia syndrome, HHS, Klotho, parathyroid hormone, PTH, hyperparathyroidism, pHPT, sHPT, uremic, vitamin D3
National Category
Endocrinology and Diabetes
Research subject
Internal Medicine
Identifiers
urn:nbn:se:uu:diva-107456 (URN)978-91-554-7590-1 (ISBN)
Public defence
2009-09-26, Hörsalen, D1, Klinisk mikrobiologi, Dag Hammarskjölds väg 17, Uppsala, 09:30 (Swedish)
Opponent
Supervisors
Available from: 2009-09-03 Created: 2009-08-12 Last updated: 2009-10-02Bibliographically approved

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