ACTIONS OF 1,25-DIHYDROXYVITAMIN D3 IN CHRONIC RENAL FAILURE

这项提议继续进行与维生素变化相关的研究。 D和甲状旁腺激素(PTH)在慢性肾功能衰竭(CRF)中的作用 具体地说，将调查两个领域：1)维生素变化 D受体的表达和作用2)肾脏的表达和调节 和肾外1-羟基酶。 甲状旁腺维生素D受体(VDR)水平降低 慢性肾功能衰竭患者和动物。降低血清1，25(OH)2D3(a VDR水平的刺激物)和增加甲状旁腺素(VDR的抑制物) 可能是VDR水平低的原因。拟议的研究将 探讨1，25-(OH)2D3和PTH在VDR调节中的作用 慢性肾功能衰竭大鼠甲状旁腺和肠道。将对VDR进行分析 1，25-(OH)2D3和DNA结合亲和力，并用1，25-(OH)2D3定量 (OH)2D3结合及Western和Northern印迹分析。文化修养 甲状旁腺细胞将被用来研究1，25- (OH)2D3、PTH等因素对VDR水平及其DNA结合的影响 亲和力。此外，还将对尿毒症患者进行研究，以 确定循环1，25-(OH)2D3本身的浓度是否具有 在抑制甲状旁腺激素中的作用。我们还将确定是否 对刚开始透析的患者给予1，25-(OH)2D3 修改继发性甲状旁腺功能亢进症的自然病史。 不同程度的维生素D缺乏与慢性肾功能衰竭有关。尽管 高甲状旁腺素，肾脏1α-羟基酶的刺激物，残留的酶是 无法补偿1，25-(OH)2D3的生产。然而，非常低的 无肾患者的1，25-(OH)2D3水平可显著升高 在25(OH)D3处理后提示底物利用率的作用 肾外1.25-(OH)2D3代。25(OH)D的亲和力 肝和外周巨噬细胞的肾外1α-羟基酶 减少尿毒症。我们将检查表达式之间的关联 肾外1-α-羟基酶活性与血清1，25-(OH)2D3的降低 随着肾功能衰竭的进展。自从规定了 肾外1α-羟基酶与肾脏有明显不同 酶，我们将研究肾外1，25-(OH)2D3的调节 生产作为一种潜在的治疗工具来防止 重度骨化三醇缺乏症与钙稳态的关系 肾功能衰竭。

This proposal continues ongoing studies related to alterations in vitamin D and parathyroid hormone (PTH) in chronic renal failure (CRF). Specifically, two areas will be investigated: 1) ALTERATIONS IN VITAMIN D RECEPTOR EXPRESSION AND ACTION 2) EXPRESSION AND REGULATION OF RENAL AND EXTRA-RENAL 1-HYDROXYLASE. Vitamin D receptor (VDR) levels are decreased in parathyroid glands of patients and animals with CRF. The decrease serum 1,25(OH)2D3 (a stimulator of VDR levels) and increase PTH (a suppressor of VDR) in CRF are likely causes of the low VDR levels. The proposed studies will examine the roles of 1,25-(OH)2D3 and PTH in the regulation of VDR in the parathyroid glands and intestine of rats with CRF. VDR will be analyzed for 1,25-(OH)2D3 and DNA binding affinity, and quantitated by 1,25- (OH)2D3 binding and by Western and Northern blot analysis. Cultured parathyroid cells will be used to examine the direct effects of 1,25- (OH)2D3, PTH, and other factors on the levels of VDR and its DNA binding affinity. In addition, studies will be performed in uremic patients to determine if the concentration of circulating 1,25-(OH)2D3 per se has a role in the suppression of PTH. We will also determine if the administration of 1,25-(OH)2D3 to patients newly starting dialysis modifies the natural history of secondary hyperparathyroidism. Various degrees of vitamin D deficiency are associated with CRF. Despite high PTH, a stimulator of renal 1alpha-hdroxylase, the remnant enzyme is unable to compensate 1,25-(OH)2D3 production. However the very low levels of 1,25-(OH)2D3 in anephric patients can rise dramatically following 25(OH)D3 treatment suggesting a role for substrate availability in extrarenal 1.25-(OH)2D3 generation. The affinity for 25(OH)D of the extrarenal 1alpha-hydroxylases of liver and peripheral macrophages is reduced in uremia. We will examine the associated between the expression of extrarenal 1-alpha-hydroxylase and the reduction in serum 1,25-(OH)2D3 with the progression of renal failure. Since the regulation of extrarenal 1 alpha-hydroxylase differs markedly from that of the renal enzyme, we will examine the modulation of extrarenal 1,25-(OH)2D3 production as a potential therapeutic tool to prevent the alterations in calcium homeostasis association with calcitriol deficiency in severe renal failure.