Regulation of bone and calcium, metabolism by bio-active substances accumulated in uremic serum.

为了探讨尿毒症血清中生物活性物质的作用，我们完成了以下研究：1. FGF 23在尿毒症继发性甲状旁腺功能亢进中的作用FGF 23是一种新发现的磷酸尿因子，与多种低磷酸血症性疾病有关。在慢性肾病中，FGF 23响应于磷负荷而分泌。其促进磷酸盐的尿排泄并抑制活性维生素D（1，25 D）的产生。在慢性肾病（CKD）中，该系统在CKD的早期阶段工作良好，但在后期阶段，肾脏不再能够排泄负载的磷酸盐。高磷酸盐血症，连同低1，25 D，刺激PTH分泌，导致甲状旁腺功能亢进。在透析患者中，FGF 23水平变得更高，主要是由于长期使用维生素D类似物。我们还发现，血清FGF 23水平可以作为难治性甲状旁腺功能亢进症的发展的预测指标。2.尿毒症毒素导致尿毒症骨转换低为了阐明尿毒症骨骼对PTH抵抗的发病机制，我们分析了甲状旁腺切除和肾部分切除的模型大鼠。骨形成的抑制依赖于肾功能不全的程度和硫酸吲哚酚的血清浓度，这是一种很好的尿毒症毒素研究。我们进一步研究了硫酸吲哚酚对体外培养成骨细胞的影响，发现硫酸吲哚酚通过有机阴离子转运蛋白转运到细胞内，诱导氧化应激，下调PTH受体，3.严重甲状旁腺功能亢进症中甲状旁腺素的新分子形式我们分析了从手术切除的甲状旁腺和血清中提取的提取物，这些提取物来自一名全甲状旁腺激素/甲状旁腺激素比值异常的患者。全段PTH通过高效液相色谱法，发现了一种新的1- 84 PTH，其可能在完整PTH测定中使用的抗体的识别位点处发生修饰。

To investigate the roles of bio-active substances accumulated in uremic serum, we complete the following projects.1.Role of FGF23 in secondary hyperparathyroidism in uremiaFGF23 is a newly discovered phosphaturic factor responsible for several hypophosphatemic diseases. In chronic kidney disease, FGF23 is secreted in response to phosphorus load., which promotes urinary excretion of phosphate and suppresses production of active vitamin D (1,25D). In chronic kidney disease (CKD), this system works well in the early stages of CKD, but in later stages, the kidney is not able to excrete loaded phosphate any more. Hyperphosphatemia, together with low 1,25D, stimulates PTH secretion, leading to hyperparathyroidism. In dialysis patients, FGF23 levels become much higher, mainly due to long-term use of vitamin D analogues. We have also shown that serum level of FGF23 can serve as an predictive marker for the development of refractory hyperparathyroidism.2.Uremic Toxins induce low turnover bone in uremiaTo elucidate the pathogenesis of skeletal resistance to PTH in uremia, we analyzed model rats made by parathyroidectomy and partial nephrectomy. Suppression of bone formation was dependent on the degree of renal dysfunction and on the serum concentration of indoxyl sulfate, a well studies uremic toxin. We further investigated the effects of indoxyl sulfate on ostaoblasts in vitro and found that indoxyl sulfate was transported into the cell by organic anion transporter and induces oxidative stress, down-regulation of PTH receptor, and disturbed response of cAMP to PTH.3.New molecular form of PTH in severe hyperparathyroidismWe analyzed extract from the surgically excised parathyroid gland and serum from a patient with abnormal ratio of whole PTH/ intact PTH. By HPLC, a new 1-84PTH with possible modification at the site of the recognition site by the antibody used in intact PTH assay was discovered.