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.

Pharmacology of AMG 416 (Velcalcetide), a Novel Peptide Agonist of the Calcium-Sensing Receptor, for the Treatment of Secondary Hyperparathyroidism in Hemodialysis Patients

“…Along with parathyroid gland hyperplasia, a decrease in expression of the CaSR (Kifor et al, 1996;Gogusev et al, 1997), FGFR1 (Canalejo et al, 2010), and VDR (Fukuda et al, 1993;Tokumoto et al, 2002) contribute to reduced responsiveness of the parathyroid gland to normal mineral and hormonal control, which helps explain the observation that parathyroid glands of SHPT patients frequently become progressively resistant to regulation by calcium and 1,25-dihydroxyvitamin D analogs (Drueke, 1995;Galitzer et al, 2009;Canalejo et al, 2010;Komaba et al, 2010). Thus, downregulation of these receptors seems to be an important contributing factor to the pathogenic progression of SHPT and further contributes to the mineral and endocrine derangements seen in these patients (Drueke et al, 2007;Komaba et al, 2010).…”

FGF-23 Levels in Patients with AKI and Risk of Adverse Outcomes

“…Accordingly, FGF-23 elevation in the setting of AKI may reflect the transient secondary hyperparathyroidism that results from hypocalcemia. However, a recent study in uremic CKD patients suggests that FGF-23 may actually be the physiologic regulator of PTH secretion (17). Clearly, elucidating the complex interplay between FGF-23, PTH, and phosphate remains critical to our understanding of mineral metabolism, and it is an area of active investigation.…”

Calcium Deficiency Reduces Circulating Levels of FGF23

“…[5][6][7] However, in uremic animals, hyperplastic parathyroid glands fail to respond to FGF23 because the expression of FGFR-klotho is downregulated. [7][8][9][10][11] FGF23 effectively increases the output and decreases the input of phosphorus because it directly increases phosphaturia and indirectly decreases intestinal phosphorus absorption by decreasing calcitriol values. However, a conflict will arise if high FGF23 inhibits calcitriol production in a setting of calcium deficiency/hypocalcemia, where high calcitriol is needed to increase intestinal calcium absorption.…”