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1,25-(OH)2D receptors are decreased in parathyroid glands from chronically uremic dogs
A J Brown1, A Dusso, S Lopez-Hilker
1Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
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.
Insights
Chronic kidney disease reduces the vitamin D receptor in parathyroid glands, potentially causing hyperparathyroidism. Lower vitamin D receptor levels correlate with increased parathyroid hormone, impairing gland response to vitamin D.
Area of Science:
- Endocrinology
- Nephrology
- Molecular Biology
Background:
- 1,25-dihydroxyvitamin D (1,25-(OH)2D) suppresses parathyroid hormone (PTH) synthesis and secretion.
- This hormonal control is mediated by the 1,25-(OH)2D receptor in target cells.
Purpose of the Study:
- To investigate the levels and characteristics of the 1,25-(OH)2D receptor in parathyroid glands of dogs with chronic renal failure.
- To determine the relationship between 1,25-(OH)2D receptor levels, vitamin D status, and PTH in uremic dogs.
Main Methods:
- Analysis of 1,25-(OH)2D receptor levels in parathyroid extracts from normal and uremic dogs.
- Assessment of receptor binding affinity and sedimentation characteristics.
- Correlation analysis between serum 1,25-(OH)2D, receptor content, and N-terminal PTH levels.
Main Results:
- Parathyroid 1,25-(OH)2D receptor levels were fourfold lower in uremic dogs compared to normal dogs.
- No significant differences were found in receptor binding affinity or sedimentation.
- Lower receptor content correlated negatively with serum N-terminal PTH levels.
Conclusions:
- Reduced 1,25-(OH)2D receptor number in uremic dogs may decrease parathyroid gland responsiveness to 1,25-(OH)2D.
- This diminished responsiveness could contribute to the hyperparathyroidism observed in chronic renal failure.