Regulation of intestinal vitamin D receptor expression in experimental uraemia: effects of parathyroidectomy and administration of PTH.
In this study, the effects of PTH on binding of [3H]-1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and on vitamin D receptor (VDR) mRNA concentration were assessed in intestinal mucosa of subtotally nephrectomized rats (Nx) and in intestinal mucosa of sham-operated rats with normal kidney function (Intact). Intestinal 1,25(OH)2D3 binding capacity of Intact remained unchanged (i) after parathyroidectomy (PTx), (ii) after administration of PTH for up to 6 days, and (iii) after PTx and subsequent administration of PTH (n = 4 experiments). In contrast, PTx of subtotally nephrectomized animals (Nx-PTx) decreased 1,25(OH)2D3 binding capacity from 757 +/- 95 fmol/mg protein in Nx to 417 +/- 42 in Nx-PTx (P < 0.01, n = 5). PTH administration had no effect on intestinal 1,25(OH)2D3 binding capacity in Nx. However, PTH administration to Nx-PTx resulted in re-elevation of 1,25(OH)2D3 binding capacity to a level (790 +/- 113 fmol/mg protein) which was comparable to Nx. Kd-values remained unaltered under all experimental conditions. The intestinal VDR mRNA concentration (normalized to beta-actin mRNA) was decreased, on average, by 23% in Nx-PTx (P < 0.05 versus Nx). In further experiments, 1,25(OH)2D3 was administered to Nx-PTx. This resulted in upregulation of 1,25(OH)2D3 binding capacity as compared to vehicle-treated Nx-PTx (562 +/- 90 fmol/mg protein versus 249 +/- 32, P < 0.01). The latter results could indicate that PTH-mediated stimulation of residual renal 1,25(OH)2D3 production was involved in PTH-mediated up-regulation of intestinal 1,25(OH)2D3 binding capacity in Nx-PTx. To rule out this possibility, PTH was administered to totally nephrectomized and parathyroidectomized rats (TNx-PTx). Since PTH caused an approximately 80% increase (P < 0.05) in intestinal 1,25(OH)2D3 binding capacity under those experimental conditions a mediator role of 1,25(OH)2D3 could be excluded. Functional significance of decreased intestinal 1,25(OH)2D3 binding capacity in Nx-PTx as compared to Nx was demonstrated by significantly lower 1,25(OH)2D3-mediated stimulation of intestinal 25(OH)D3-24-hydroxylase activity in Nx-PTx (209 +/- 68 pmol/mg protein) than in Nx (385 +/- 81, P < 0.01). The modulation of intestinal 1,25(OH)2D3 binding capacity was not correlated with changes in calcium, phosphate or 1,25(OH)2D3 serum concentrations under our experimental conditions. Taken together, intact parathyroid gland function was required to maintain adequate intestinal VDR expression in experimental uraemia (but not in normal animals). The mechanism of the modulation of intestinal VDR by PTH remains to be elucidated although an indirect effect of PTH on VDR expression in intestinal mucosa seems most likely.
Szabó
A
A
Department of Internal Medicine, University of Heidelberg, Germany.
Schmutz
A
A
Pesian
S
S
Schmidt-Gayk
H
H
Ritz
E
E
Reichel
H
H
D000818:Animals; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System; D007413:Intestinal Mucosa / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism; D008297:Male; D009392:Nephrectomy; D009994:Osmolar Concentration; D010281:Parathyroid Hormone / Q000494:pharmacology*; D016105:Parathyroidectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism; D014511:Uremia / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol