NDT Advance Access originally published online on December 21, 2007
Nephrology Dialysis Transplantation 2008 23(5):1529-1536; doi:10.1093/ndt/gfm850
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Highly concentrated calcitriol and its analogues induce apoptosis of parathyroid cells and regression of the hyperplastic gland—study in rats*
1 Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke 329-0498 2 The First Department of Pathology, Wakayama Medical University, Wakayama 641-0012 3 Division of Nephrology and Center of Blood Purification Therapy, Wakayama Medical University, Wakayama 641-0012 4 Medical Section, Sendai Branch, Chugai Pharmaceutical Co. Ltd, Sendai 980-0014 5 Department of Nephrology, Showa University School of Medicine, Tokyo 142-0064, Japan
Correspondence and offprint requests to: Kazuhiro Shiizaki, Division of Nephrology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Tel: +81-285-58-7346; Fax: +81-285-44-4869; E-mail: shiizaki{at}jichi.ac.jp
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Abstract |
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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.
Keywords: cell death; electron microscopy; hyperparathyroidism; renal osteodystrophy; vitamin D
* Part of this study was presented at the Annual Meeting of the American Society of Nephrology, Philadelphia, PA, USA, 2005, and appeared as an abstract (J Am Soc Nephrol 2005; 16: 494A).
Received for publication: 17. 7.07
Accepted in revised form: 5.11.07
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