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Biochemical and Cellular Effects of Direct Maxacalcitol Injection into Parathyroid Gland in Uremic Rats

Kazuhiro Shiizaki^*, Shigeo Negi^*, Ikuji Hatamura, Toshifumi Sakaguchi^*, Fumie Saji^*, Ken Kunimoto^*, Masahide Mizobuchi^*, Ikuo Imazeki, Akira Ooshima and Tadao Akizawa^*

^* Center of Blood Purification Therapy and The First Department of Pathology, Wakayama Medical University, Wakayama; and Product Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan

Address correspondence to: Dr. Kazuhiro Shiizaki, Center of Blood Purification Therapy, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan. Phone and Fax: +81-73-441-0639; E-mail: shiizaki{at}wakayama-med.ac.jp

The most important etiological factors of resistance to medical treatments for secondary hyperparathyroidism are the decreased contents of the vitamin D receptor (VDR) and Ca-sensing receptor (CaSR) in parathyroid cells and a severely swollen parathyroid gland (PTG) as a result of hyperplasia. The effects of direct maxacalcitol (OCT) injection into PTG in terms of these factors were investigated in this study. The PTG of Sprague-Dawley rats that were 5/6 nephrectomized and fed a high-phosphate diet were treated by a direct injection of OCT (DI-OCT) or vehicle (DI-vehicle). The changes in serum intact parathyroid hormone (PTH), Ca²⁺, and phosphorus levels, in VDR and CaSR expression levels in parathyroid cells, and in Ca²⁺-PTH curves were examined. Apoptosis was analyzed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method and DNA electrophoresis for PTG. DI-OCT markedly decreased serum intact PTH level, and a significant difference in this level between DI-OCT and DI-vehicle was observed. However, serum Ca²⁺ and phosphorus levels did not changed markedly in both groups. The upregulations of both VDR and CaSR, the clear shift to the left downward in the Ca²⁺-PTH curve, and the induction of apoptosis after DI-OCT were observed. These findings were not observed in the DI-vehicle-treated rats. Moreover, these effects of DI-OCT were confirmed by the DI-OCT into one PTG and DI-vehicle alone into another PTG in the same rat. DI-OCT may introduce simultaneous VDR and CaSR upregulations and the regression of hyperplastic PTG, and these effects may provide a strategy for strongly suppressing PTH levels in very severe secondary hyperparathyroidism.

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