The mechanism by which resistance to 1,25-(OH)2D3 occurs in patients with chronic renal failure was studied. 1,25-(OH)2D3 causes the induction of differentiation and of 1,25-(OH)2D3-24-hydroxylase activity in the mitochondria of the human promyelocytic leukemia cell line, HL-60, via a steroid hormone-receptor mechanism. Treatment of these cells with 10 8M 1,25-(OH)2D3 for 5 days in a medium containing 10% uremic serum from 4 patients with chronic renal failure resulted in maturation of the cells amounting to 30.3 ± 18.7 (mean ± SD) and 32.5 ± 11.2% maturation by the nitroblue tetrazolium reduction assay and the nonspecific esterase assay, respectively. These values were significantly lower than those obtained with 10% normal serum from 3 normal controls (66.6 ± 12.8 and 58.3 ± 10.9%, p < 0.02). The occurrence of resistance to 1,25-(OH)2D3 in uremic serum-treated cells was also confirmed when the effect of 1,25-(OH)2D3 was assessed by the induction of the cell’s ability to hydroxylate the C-24 position of 1,25-(OH)2[3H]D3. Treatment of HL-60 cells with a mixture of 5% uremic plus 5% normal serum impaired 1,25-(OH)2D3-induced cell differentiation to the levels as those in 10% uremic serum, strongly suggesting the occurrence of a substance(s) having 1,25-(OH)2D3-inhibitory activity in the uremic serum. A significant reduction in 1,25-(OH)2D3 receptor levels was observed in uremic serum-treated cells. We have recently reported that the addition of dibutyryl cAMP significantly enhances the effect of l,25-(OH)2D3 on HL-60 cells by increasing 1,25-(OH)2D3 receptor levels and that a significant positive correlation was observed between intracellular cAMP levels and 1,25-(OH)2D3-induced HL-60 cell maturation. Together with the data that treatment of the cells with uremic serum resulted in a significant reduction in intracellular cAMP levels, the significance of cAMP in the occurrence of 1,25-(OH)2D3-resistance in uremic serum-treated cells is indicated.

Keywords:
Uremia, 1,25-(OH)2D3, HL-60 cells, Differentiation, Resistance
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© 1993 S. Karger AG, Basel
1993
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