Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Dec 15;100(12):2977–2983. doi: 10.1172/JCI119851

The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor.

M Wada 1, Y Furuya 1, J Sakiyama 1, N Kobayashi 1, S Miyata 1, H Ishii 1, N Nagano 1
PMCID: PMC508509  PMID: 9399943

Abstract

Parathyroid (PT) cell hyperplasia is a common consequence of chronic renal insufficiency (CRI). NPS R-568 is a phenylalkylamine compound that acts as an agonist (calcimimetic) at the cell surface calcium receptor (CaR). To test the hypothesis that the CaR plays a role in PT hyperplasia in CRI, we tested the effect of NPS R-568 on PT cell proliferation in rats with renal insufficiency. Rats were subjected to 5/6 nephrectomy and then infused intraperitoneally with 5-bromodeoxyuridine (BrdU) to label S-phase cells. Two groups of nephrectomized rats received NPS R-568 by gavage twice daily for 4 d (1.5 and 15 mg/kg body wt). On day 5, the number of BrdU-positive PT cells of vehicle-treated nephrectomized rats was 2.6-fold greater than that of the sham-operated control. Low and high doses of NPS R-568 reduced the number of BrdU-positive PT cells by 20 and 50%, respectively. No changes in staining, however, were observed in ileal epithelial cells (CaR-negative) or in thyroidal C-cells (CaR-positive). Furthermore, the effect of NPS R-568 could not be explained by changes in serum 1,25(OH)2D3 or phosphorus. These results indicate that NPS R-568 suppresses PT cell proliferation in rats with renal insufficiency, and lend support to the linkage between the CaR and PT hyperplasia in CRI.

Full Text

The Full Text of this article is available as a PDF (474.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bianchi S., Fabiani S., Muratori M., Arnold A., Sakaguchi K., Miki T., Brandi M. L. Calcium modulates the cyclin D1 expression in a rat parathyroid cell line. Biochem Biophys Res Commun. 1994 Oct 28;204(2):691–700. doi: 10.1006/bbrc.1994.2515. [DOI] [PubMed] [Google Scholar]
  2. Brandi M. L., Fitzpatrick L. A., Coon H. G., Aurbach G. D. Bovine parathyroid cells: cultures maintained for more than 140 population doublings. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1709–1713. doi: 10.1073/pnas.83.6.1709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown E. M. Extracellular Ca2+ sensing, regulation of parathyroid cell function, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev. 1991 Apr;71(2):371–411. doi: 10.1152/physrev.1991.71.2.371. [DOI] [PubMed] [Google Scholar]
  4. Brown E. M., Gamba G., Riccardi D., Lombardi M., Butters R., Kifor O., Sun A., Hediger M. A., Lytton J., Hebert S. C. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature. 1993 Dec 9;366(6455):575–580. doi: 10.1038/366575a0. [DOI] [PubMed] [Google Scholar]
  5. Brown E. M., Pollak M., Seidman C. E., Seidman J. G., Chou Y. H., Riccardi D., Hebert S. C. Calcium-ion-sensing cell-surface receptors. N Engl J Med. 1995 Jul 27;333(4):234–240. doi: 10.1056/NEJM199507273330407. [DOI] [PubMed] [Google Scholar]
  6. Chattopadhyay N., Mithal A., Brown E. M. The calcium-sensing receptor: a window into the physiology and pathophysiology of mineral ion metabolism. Endocr Rev. 1996 Aug;17(4):289–307. doi: 10.1210/edrv-17-4-289. [DOI] [PubMed] [Google Scholar]
  7. Daub H., Weiss F. U., Wallasch C., Ullrich A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature. 1996 Feb 8;379(6565):557–560. doi: 10.1038/379557a0. [DOI] [PubMed] [Google Scholar]
  8. Denda M., Finch J., Slatopolsky E. Phosphorus accelerates the development of parathyroid hyperplasia and secondary hyperparathyroidism in rats with renal failure. Am J Kidney Dis. 1996 Oct;28(4):596–602. doi: 10.1016/s0272-6386(96)90473-4. [DOI] [PubMed] [Google Scholar]
  9. Dikic I., Tokiwa G., Lev S., Courtneidge S. A., Schlessinger J. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature. 1996 Oct 10;383(6600):547–550. doi: 10.1038/383547a0. [DOI] [PubMed] [Google Scholar]
  10. Drüeke T. B. The pathogenesis of parathyroid gland hyperplasia in chronic renal failure. Kidney Int. 1995 Jul;48(1):259–272. doi: 10.1038/ki.1995.292. [DOI] [PubMed] [Google Scholar]
  11. Freichel M., Zink-Lorenz A., Holloschi A., Hafner M., Flockerzi V., Raue F. Expression of a calcium-sensing receptor in a human medullary thyroid carcinoma cell line and its contribution to calcitonin secretion. Endocrinology. 1996 Sep;137(9):3842–3848. doi: 10.1210/endo.137.9.8756555. [DOI] [PubMed] [Google Scholar]
  12. Garrett J. E., Tamir H., Kifor O., Simin R. T., Rogers K. V., Mithal A., Gagel R. F., Brown E. M. Calcitonin-secreting cells of the thyroid express an extracellular calcium receptor gene. Endocrinology. 1995 Nov;136(11):5202–5211. doi: 10.1210/endo.136.11.7588259. [DOI] [PubMed] [Google Scholar]
  13. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gogusev J., Duchambon P., Hory B., Giovannini M., Goureau Y., Sarfati E., Drüeke T. B. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int. 1997 Jan;51(1):328–336. doi: 10.1038/ki.1997.41. [DOI] [PubMed] [Google Scholar]
  15. Gundersen H. J., Jensen E. B. Stereological estimation of the volume-weighted mean volume of arbitrary particles observed on random sections. J Microsc. 1985 May;138(Pt 2):127–142. doi: 10.1111/j.1365-2818.1985.tb02607.x. [DOI] [PubMed] [Google Scholar]
  16. Hansson C. G., Mathewson S., Norrby K. Parathyroid cell growth and proliferation in nephrectomised rats. Pathol Eur. 1971;6(3):313–321. [PubMed] [Google Scholar]
  17. Hasegawa K., Turner C. H., Recker R. R., Wu E., Burr D. B. Elastic properties of osteoporotic bone measured by scanning acoustic microscopy. Bone. 1995 Jan;16(1):85–90. doi: 10.1016/s8756-3282(94)00013-1. [DOI] [PubMed] [Google Scholar]
  18. Ho C., Conner D. A., Pollak M. R., Ladd D. J., Kifor O., Warren H. B., Brown E. M., Seidman J. G., Seidman C. E. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet. 1995 Dec;11(4):389–394. doi: 10.1038/ng1295-389. [DOI] [PubMed] [Google Scholar]
  19. Ishimi Y., Russell J., Sherwood L. M. Regulation by calcium and 1,25-(OH)2D3 of cell proliferation and function of bovine parathyroid cells in culture. J Bone Miner Res. 1990 Jul;5(7):755–760. doi: 10.1002/jbmr.5650050712. [DOI] [PubMed] [Google Scholar]
  20. Kifor O., Moore F. D., Jr, Wang P., Goldstein M., Vassilev P., Kifor I., Hebert S. C., Brown E. M. Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab. 1996 Apr;81(4):1598–1606. doi: 10.1210/jcem.81.4.8636374. [DOI] [PubMed] [Google Scholar]
  21. Kremer R., Bolivar I., Goltzman D., Hendy G. N. Influence of calcium and 1,25-dihydroxycholecalciferol on proliferation and proto-oncogene expression in primary cultures of bovine parathyroid cells. Endocrinology. 1989 Aug;125(2):935–941. doi: 10.1210/endo-125-2-935. [DOI] [PubMed] [Google Scholar]
  22. Naveh-Many T., Rahamimov R., Livni N., Silver J. Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J Clin Invest. 1995 Oct;96(4):1786–1793. doi: 10.1172/JCI118224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. RAISZ L. G. Regulation by calcium of parathyroid growth and secretion in vitro. Nature. 1963 Mar 16;197:1115–1116. doi: 10.1038/1971115a0. [DOI] [PubMed] [Google Scholar]
  24. Slatopolsky E., Finch J., Denda M., Ritter C., Zhong M., Dusso A., MacDonald P. N., Brown A. J. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest. 1996 Jun 1;97(11):2534–2540. doi: 10.1172/JCI118701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Szabo A., Merke J., Beier E., Mall G., Ritz E. 1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia. Kidney Int. 1989 Apr;35(4):1049–1056. doi: 10.1038/ki.1989.89. [DOI] [PubMed] [Google Scholar]
  26. TALMAGE R. V., TOFT R. J., DAVIS R. Parathyroid activity in nephrectomized rats. Tex Rep Biol Med. 1960;18:298–308. [PubMed] [Google Scholar]
  27. Tominaga Y., Takagi H. Molecular genetics of hyperparathyroid disease. Curr Opin Nephrol Hypertens. 1996 Jul;5(4):336–341. doi: 10.1097/00041552-199607000-00008. [DOI] [PubMed] [Google Scholar]
  28. Wan Y., Kurosaki T., Huang X. Y. Tyrosine kinases in activation of the MAP kinase cascade by G-protein-coupled receptors. Nature. 1996 Apr 11;380(6574):541–544. doi: 10.1038/380541a0. [DOI] [PubMed] [Google Scholar]
  29. Wernerson A., Svensson O., Reinholt F. P. Parathyroid cell number and size in hypercalcemic rats: a stereologic study employing modern unbiased estimators. J Bone Miner Res. 1989 Oct;4(5):705–713. doi: 10.1002/jbmr.5650040509. [DOI] [PubMed] [Google Scholar]
  30. Wernerson A., Svensson O., Reinholt F. P. Quantitative and three-dimensional aspects of the rat parathyroid gland in normo-, hypo-, and hypercalcemia. Microsc Res Tech. 1995 Oct 1;32(2):129–147. doi: 10.1002/jemt.1070320208. [DOI] [PubMed] [Google Scholar]
  31. Wernerson A., Widholm S. M., Svensson O., Reinholt F. P. Parathyroid cell number and size in hypocalcemic young rats. APMIS. 1991 Dec;99(12):1096–1102. doi: 10.1111/j.1699-0463.1991.tb01306.x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES