Abnormal Expression and Regulation of Vitamin D Receptor in Experimental Uremia

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Abstract
The low concentration of the biologically active metabolite of vitamin D, namely lα,25-dihydroxyvitamin D3 (1,25(OH)2D3), is critical to the pathogenesis of secondary hyperparathyroidism in chronic renal failure. The actions of 1,25(OH)2D3 are mediated through binding to a cellular receptor protein, the vitamin D receptor (VDR). In order to further investigate expression and regulation of VDR in uremia, we measured specific [3H]-1,25(OH)2D3 binding capacity and VDR mRNA concentration in intestinal mucosa and in parathyroid glands of subtotally nephrectomized rats (Nx) and compared Nx to sham-operated rats with normal kidney function (Intact). Intestinal [3H]-1,25(OH)2D3 binding capacity in short-term Nx (6-10 days after nephrectomy) was 663 ± 114 fmol/mg protein; it was 517 ± 34 in Intact (p = 0.06, n = 6 experiments). Intestinal VDR mRNA concentration was comparable between Nx and Intact. Specific 1,25(OH)2D3 binding capacity in parathyroid glands was higher in Nx (195 ± 9 fmol/mg protein) than in Intact (116 ± 14 fmol/mg protein, n = 5, p 2D3 (KD) did not change in Nx. The 1,25(OH)2D3 binding capacity in intestinal mucosa of more long-term uremic animals (14-16 weeks after subtotal Nx) was 519 ± 32 fmol/mg protein versus 349 ± 31 in Intact (n = 3, p 2D3 binding capacity in uremic rats with hereditary polycystic kidney disease was compared to control rats with normal kidney function (757 ± 54 fmol/mg protein versus 495 ± 59 in intestinal mucosa, p 2D3 binding capacity, 1,25(OH)2D3-mediated stimulation of intestinal 25(OH)D3-24-hydroxylase activity was significantly higher in long-term subtotally Nx (1.43 ± 0.06 pmol 24,25-dihydroxyvitamin D3/mg protein) than in sham-operated normal rats (1.04 ± 0.10, p 2D3 to sham-operated normal rats resulted in an increase of 1,25(OH)2D3 binding capacity by 20-40% in intestinal mucosa and by 40-50% in parathyroid glands. In contrast, 1,25(OH)2D3 caused down-regulation of mean 1,25(OH)2D3 binding capacity in short-term Nx by 38% in intestinal mucosa (p 2D3 binding capacity was reduced by 20% in intestinal mucosa (p 2D3 for 6 weeks, intestinal 1,25(OH)2D3 binding capacity was markedly down-regulated in uremic rats (43% versus vehicle-treated animals, p 2D3 in renal insufficiency.

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