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Endothelin Receptor Antagonist Prevents Parathyroid Cell Proliferation of Low Calcium Diet-Induced Hyperparathyroidism in Rats

Department of Internal Medicine 3, Kumamoto University School of Medicine, 1–1-1 Honjo, Kumamoto 860-8556, Japan

Address all correspondence and requests for reprints to: Hiroshi Tokunaga, M.D., Department of Internal Medicine 3, Kumamoto University School of Medicine, 1–1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: tokunaga{at}kaiju.medic.kumamoto-u.ac.jp

Secondary hyperparathyroidism, one of the most frequently encountered disorders of the calcium homeostasis, is characterized by an increase in parathyroid epithelial (PT) cell number, which is crucial from a functional viewpoint. However, it is still unknown what factors are involved in PT cell proliferation. Endothelin-1 (ET-1), a vasoconstrictive peptide, has been shown to act as a mitogen in a variety of cell types. Rat PT cells are reported to synthesize ET-1 and possess its receptors. To test the hypothesis that ET-1 plays a role in PT cell proliferation, we used rat test subjects fed a low calcium diet for 8 weeks (low Ca rats). The number of the proliferating PT cells, measured by proliferating cell nuclear antigen immunostaining, was significantly increased, with striking immunoreactivity of ET-1 in the low Ca rats. An endothelin receptor antagonist, bosentan (100 mg/kg·day), prevented any increase in the proliferation of PT cells in the low Ca rats (14.3 ± 2.7/1000 PT cells with no bosentan; 2.1 ± 1.3 with bosentan; P < 0.01). These results indicate that ET-1 is involved in PT cell proliferation in vivo and suggest that blocking of ET receptors may become one of the important therapeutic strategies for preventing secondary hyperparathyroidism.

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