1,25-(OH)2D receptors are decreased in parathyroid glands from chronically uremic dogs

Abstract

1,25-(OH)2D has been shown to suppress the synthesis and secretion of parathyroid hormone in vivo and in dispersed parathyroid cell cultures. Control of transcription by 1,25-(OH)2D is believed to be mediated by interaction of this hormone with a specific receptor within target cells. We have examined the 1,25-(OH)2D receptor in parathyroid glands from normal dogs and chronic renal failure dogs. The levels of receptor were fourfold lower in parathyroid extracts from these uremic dogs than in those from normal dogs (109 +/- 11 vs. 446 +/- 61 fmol/mg protein). No differences were observed in the binding affinity for 1,25-(OH)2D or in the sedimentation in sucrose density gradients. Since this receptor has been shown to be upregulated by 1,25-(OH)2D, our findings of lower levels of receptor could be attributed to decreased serum concentrations of 1,25-(OH)2D in chronically uremic animals. Regression analysis of log serum 1,25-(OH)2D versus log receptor content yielded a correlation coefficient of 0.62 with P less than 0.02. Decreased receptor content showed a negative correlation with serum N-terminal PTH (r = 0.71 and P less than 0.01). It is likely that this reduced 1,25-(OH)2D receptor number in the parathyroid glands of chronically uremic animals renders the glands less responsive to the inhibitory action of 1,25-(OH)2D on the synthesis and secretion of PTH, and may contribute to the hyperparathyroidism associated with chronic renal failure.

Long-Term Suppression of Secondary Hyperparathyroidism by Intravenous 1α-Hydroxy vitamin D₃ in Patients on Chronic Hemodialysis

“…1,25(OH)2D3 appears to be the major factor controlling PTH gene transcription in the parathyroid glands [16,17]. Insensitivity to the suppres sive effect of calcium on the parathyroid glands has been demonstrated [ 18], and decreased receptor content [ 19,20] and altered or decreased significantly specific binding capacity of the uremic glands for l,25(OH)2D3 compared to normal human glands [21 ]may be of importance in the development of the changed set-point for calcium. The effect of renal failure on the skeleton can be observed already in the early phase of renal insufficiency, and renal osteodystrophy progresses insidiously for sev eral years before the patients become symptomatic.…”

Comparison of the Effects of Daily and Intermittent‐Dose Calcitriol on Serum Parathyroid Hormone and Ionized Calcium Concentrations in Normal Cats and Cats with Chronic Renal Failure

“…6 Decreased production of calcitriol also impairs intestinal absorption of calcium and further contributes to hypocalcemia and stimulation of PTH secretion by the parathyroid glands (PTG). In addition, the uremic state is associated with impaired negative feedback of calcitriol on the PTG as a result of decreased numbers of vitamin D receptors (VDR) [7][8][9] and impaired binding of the calcitriol-VDR complex with vitamin D response elements in genomic DNA of PTG cells. 10 Phosphorus retention also increases PTH synthesis and secretion by stabilizing PTH mRNA, and retained phosphorus may stimulate parathyroid cell growth.…”

Suppression of the Human Parathyroid Hormone Promoter by Vitamin D Involves Displacement of NF-Y Binding to the Vitamin D Response Element

“…NF-Y is known to synergize with Sp1 to enhance gene transcription (27,35,36), suggesting that the proximal NF-Y-binding site in the hPTH promoter may also be capable of interacting with Sp proteins bound to the upstream Sp1 DNA element. Finally, renal insufficiency is often accompanied by the development of secondary hyperparathyroidism, which has been associated with decreased vitamin D activity in the PTG (37)(38)(39)(40)(41)(42). Our data imply that unopposed NF-Y transactivation of the human promoter may be contributing to this condition; therefore drugs that attenuate NF-Y transcriptional activity may be candidates for use in treating this disorder (43,44).…”