TY - JOUR
T1 - Highly concentrated calcitriol and its analogues induce apoptosis of parathyroid cells and regression of the hyperplastic gland - Study in rats
AU - Shiizaki, Kazuhiro
AU - Hatamura, Ikuji
AU - Negi, Shigeo
AU - Sakaguchi, Toshifumi
AU - Saji, Fumie
AU - Imazeki, Ikuo
AU - Kusano, Eiji
AU - Shigematsu, Takashi
AU - Akizawa, Tadao
N1 - Funding Information:
Acknowledgements. This study was supported by Chugai Pharmaceutical Co. Ltd, Tokyo, Japan. The authors thank Kirin Brewery Co. Ltd, Tokyo, Japan and Chugai Pharmaceutical Co. Ltd for providing the calcitriol and maxacalcitol solutions, respectively.
PY - 2008/5
Y1 - 2008/5
N2 - Background. Controlling hyperplasia of the parathyroid gland (PTG) is important in the management of secondary hyperparathyroidism (SHPT). Regression of the hyperplastic PTG requires a decrease in the number of parathyroid cells (PTCs), so the present study investigated cell death caused by toxic agents or by clinically usable vitamin D metabolites. Methods. The PTGs of Sprague-Dawley rats, which had been 5/6-nephrectomized and fed a high-phosphate diet for 12 weeks, were treated with two consecutive direct injections (DI) of calcitriol, maxacalcitol, paricalcitol, doxercalciferol or phosphate-buffered saline containing either 0.01% or 90% ethanol (0.01-ET or 90-ET, respectively). Laboratory data, including serum levels of intact parathyroid hormone (intact-PTH), were obtained before and after the treatments. The PTGs were excised 24 h after the final injection and evaluated for PTC apoptosis using light and electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) method and DNA electrophoresis. Results. Treatment with any of the vitamin D metabolites and 90-ET significantly decreased the serum intact-PTH level, but only the latter significantly decreased the serum Ca level. Either treatment markedly increased the number of TUNEL-positive PTCs, but not in PTG treated with 0.01-ET. In PTGs treated with DI of any vitamin D metabolites was there ladder formation on DNA electrophoresis, as well as the characteristic morphological features of apoptosis in both the light and electron microscopic studies. Conclusions. DI of vitamin D metabolites may be effective in controlling not only the PTH level, but also PTG hyperplasia, in advanced SHPT by, at least in part, apoptosis-induced cell death. Our study was performed in rats.
AB - Background. Controlling hyperplasia of the parathyroid gland (PTG) is important in the management of secondary hyperparathyroidism (SHPT). Regression of the hyperplastic PTG requires a decrease in the number of parathyroid cells (PTCs), so the present study investigated cell death caused by toxic agents or by clinically usable vitamin D metabolites. Methods. The PTGs of Sprague-Dawley rats, which had been 5/6-nephrectomized and fed a high-phosphate diet for 12 weeks, were treated with two consecutive direct injections (DI) of calcitriol, maxacalcitol, paricalcitol, doxercalciferol or phosphate-buffered saline containing either 0.01% or 90% ethanol (0.01-ET or 90-ET, respectively). Laboratory data, including serum levels of intact parathyroid hormone (intact-PTH), were obtained before and after the treatments. The PTGs were excised 24 h after the final injection and evaluated for PTC apoptosis using light and electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) method and DNA electrophoresis. Results. Treatment with any of the vitamin D metabolites and 90-ET significantly decreased the serum intact-PTH level, but only the latter significantly decreased the serum Ca level. Either treatment markedly increased the number of TUNEL-positive PTCs, but not in PTG treated with 0.01-ET. In PTGs treated with DI of any vitamin D metabolites was there ladder formation on DNA electrophoresis, as well as the characteristic morphological features of apoptosis in both the light and electron microscopic studies. Conclusions. DI of vitamin D metabolites may be effective in controlling not only the PTH level, but also PTG hyperplasia, in advanced SHPT by, at least in part, apoptosis-induced cell death. Our study was performed in rats.
KW - Cell death
KW - Electron microscopy
KW - Hyperparathyroidism
KW - Renal osteodystrophy
KW - Vitamin D
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U2 - 10.1093/ndt/gfm850
DO - 10.1093/ndt/gfm850
M3 - Article
C2 - 18156462
AN - SCOPUS:44449100111
SN - 0931-0509
VL - 23
SP - 1529
EP - 1536
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 5
ER -