Biochemical and cellular effects of direct maxacalcitol injection into parathyroid gland in uremic rats.
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), Ca(2+), and phosphorus levels, in VDR and CaSR expression levels in parathyroid cells, and in Ca(2+)-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 Ca(2+) 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 Ca(2+)-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.
Shiizaki
Kazuhiro
K
Center of Blood Purification Therapy, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan. shiizaki@wakayama-med.ac.jp
Negi
Shigeo
S
Hatamura
Ikuji
I
Sakaguchi
Toshifumi
T
Saji
Fumie
F
Kunimoto
Ken
K
Mizobuchi
Masahide
M
Imazeki
Ikuo
I
Ooshima
Akira
A
Akizawa
Tadao
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy* / Q000473:pathology; D015552:Injections, Intralesional; D008297:Male; D010280:Parathyroid Glands / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000235:genetics; D044169:Receptors, Calcium-Sensing / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014511:Uremia / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing; D002117:Calcitriol; C051883:maxacalcitol; D002118:Calcium