| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
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 uremia
FGF23 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 uremia
To 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 hyperparathyroidism
We 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.
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