Molecular and Morphological Approach of Uremia-induced Hyperplastic Parathyroid Gland Following Direct Maxacalcitol Injection

Overview

Journal Med Mol Morphol

Publisher Springer

Specialties Cell Biology
Molecular Biology
Pathology

Date 2008 Jul 2

PMID 18592161

Authors

Kazuhiro Shiizaki

Ikuji Hatamura

Eiko Nakazawa

Manabu Ogura

Takahiro Masuda

Tadao Akizawa

Eiji Kusano

Affiliations

Soon will be listed here.

Abstract

The mechanisms explaining the clinical effects of direct maxacalcitol (OCT) injection into the hyperplastic parathyroid gland (PTG) in uremic patients with advanced secondary hyperparathyroidism (SHPT) were investigated by molecular and morphological examination. PTG of uremia-induced SHPT model rats were treated by a direct injection of OCT (DI-OCT) or vehicle (DI-vehicle). The changes in serum intact parathyroid hormone (intact-PTH) level, vitamin D and Ca-sensing receptor (VDR and CaSR, respectively) expression levels in PTG, and the calcium (Ca)-PTH response curve were examined; the induction of apoptosis in parathyroid cells (PTC) was also analyzed by the TUNEL method, DNA electrophoresis, and electron microscopic examination. Serum intact-PTH level following DI-OCT significantly decreased. Upregulation of both VDR and CaSR, a clear shift to the left downward in the Ca-PTH curve, and many apoptotic PTCs were observed in the DI-OCT-treated PTGs. However, these findings were not observed in the DI-vehicle-treated PTGs. Moreover, these effects 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 upregulation and the regression of hyperplastic PTG, and these effects may provide a strategy for strongly suppressing PTH level in uremia-induced advanced SHPT.

References

Quarles L, Yohay D, Carroll B, Spritzer C, Minda S, Bartholomay D . Prospective trial of pulse oral versus intravenous calcitriol treatment of hyperparathyroidism in ESRD. Kidney Int. 1994; 45(6):1710-21. DOI: 10.1038/ki.1994.223. View

Gogusev J, Duchambon P, Hory B, Giovannini M, Goureau Y, Sarfati E . Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int. 1997; 51(1):328-36. DOI: 10.1038/ki.1997.41. View

Shiizaki K, Fukagawa M, Yuan Q, Hatamura I, Nii-Kono T, Saji F . Direct injection of calcitriol or its analog improves abnormal gene expression in the hyperplastic parathyroid gland in uremia. Am J Nephrol. 2007; 28(1):59-66. DOI: 10.1159/000109240. View

Stumpf W . Techniques for the autoradiography of diffusible compounds. Methods Cell Biol. 1976; 13:171-93. DOI: 10.1016/s0091-679x(08)61802-6. View

Slatopolsky E, Cozzolino M, Lu Y, Finch J, Dusso A, Staniforth M . Efficacy of 19-Nor-1,25-(OH)2D2 in the prevention and treatment of hyperparathyroid bone disease in experimental uremia. Kidney Int. 2003; 63(6):2020-7. DOI: 10.1046/j.1523-1755.2003.00029.x. View

Rodriguez M, Almaden Y, Canadillas S, Canalejo A, Siendones E, Lopez I . The calcimimetic R-568 increases vitamin D receptor expression in rat parathyroid glands. Am J Physiol Renal Physiol. 2007; 292(5):F1390-5. DOI: 10.1152/ajprenal.00262.2006. View

Charhon S, Berland Y, Olmer M, Delawari E, Traeger J, Meunier P . Effects of parathyroidectomy on bone formation and mineralization in hemodialyzed patients. Kidney Int. 1985; 27(2):426-35. DOI: 10.1038/ki.1985.27. View

Shiizaki K, Hatamura I, Negi S, Sakaguchi T, Saji F, Imazeki I . Highly concentrated calcitriol and its analogues induce apoptosis of parathyroid cells and regression of the hyperplastic gland--study in rats. Nephrol Dial Transplant. 2007; 23(5):1529-36. DOI: 10.1093/ndt/gfm850. View

London G, Marty C, Marchais S, Guerin A, Metivier F, de Vernejoul M . Arterial calcifications and bone histomorphometry in end-stage renal disease. J Am Soc Nephrol. 2004; 15(7):1943-51. DOI: 10.1097/01.asn.0000129337.50739.48. View

10.

Fukuda N, Tanaka H, Tominaga Y, Fukagawa M, Kurokawa K, Seino Y . Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest. 1993; 92(3):1436-43. PMC: 288288. DOI: 10.1172/JCI116720. View

11.

Shiizaki K, Negi S, Mizobuchi M, Hatamura I, Narukawa N, Sakaguchi T . Effect of percutaneous calcitriol injection therapy on secondary hyperparathyroidism in uraemic patients. Nephrol Dial Transplant. 2003; 18 Suppl 3:iii42-6. DOI: 10.1093/ndt/gfg1011. View

12.

Shiizaki K, Negi S, Hatamura I, Tatsuta K, Shibata M, Shimada S . Direct injection of calcitriol or its analog into hyperplastic parathyroid glands induces apoptosis of parathyroid cells. Kidney Int Suppl. 2006; (102):S12-5. DOI: 10.1038/sj.ki.5001596. View

13.

Patel S, Ke H, Hsu C . Regulation of calcitriol receptor and its mRNA in normal and renal failure rats. Kidney Int. 1994; 45(4):1020-7. DOI: 10.1038/ki.1994.138. View

14.

Levine B, Song M . Pharmacokinetics and efficacy of pulse oral versus intravenous calcitriol in hemodialysis patients. J Am Soc Nephrol. 1996; 7(3):488-96. DOI: 10.1681/ASN.V73488. View

15.

Monier-Faugere M, Geng Z, FRIEDLER R, Qi Q, Kubodera N, Slatopolsky E . 22-oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure. Kidney Int. 1999; 55(3):821-32. DOI: 10.1046/j.1523-1755.1999.055003821.x. View

16.

Koike N, Hayakawa N, Tokuda K, Nishimiya K, Saito K, Stumpf W . In vivo time-course of receptor binding in the parathyroid gland of the vitamin D analogue [(3)H]1,25-dihydroxy-22-oxavitamin D(3) compared with [(3)H]1,25-dihydroxyvitamin D(3), determined by micro-autoradiography. Nephrol Dial Transplant. 2002; 17 Suppl 10:53-7. DOI: 10.1093/ndt/17.suppl_10.53. View

17.

Fukagawa M, Okazaki R, Takano K, Kaname S, Ogata E, Kitaoka M . Regression of parathyroid hyperplasia by calcitriol-pulse therapy in patients on long-term dialysis. N Engl J Med. 1990; 323(6):421-2. DOI: 10.1056/NEJM199008093230617. View

18.

Brown A, Ritter C, Finch J, Morrissey J, Martin K, Murayama E . The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion. J Clin Invest. 1989; 84(3):728-32. PMC: 329712. DOI: 10.1172/JCI114229. View

19.

Canaff L, Hendy G . Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J Biol Chem. 2002; 277(33):30337-50. DOI: 10.1074/jbc.M201804200. View

20.

Lewin E, Garfia B, Recio F, Rodriguez M, Olgaard K . Persistent downregulation of calcium-sensing receptor mRNA in rat parathyroids when severe secondary hyperparathyroidism is reversed by an isogenic kidney transplantation. J Am Soc Nephrol. 2002; 13(8):2110-6. DOI: 10.1097/01.asn.0000024439.38838.03. View