Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism.
BACKGROUND
Secondary hyperparathyroidism (HPT) in chronic kidney disease (CKD) is a physiologic response to kidney failure characterized by elevated serum parathyroid hormone (PTH) levels and parathyroid gland enlargement. Calcimimetic agents acting through allosteric modification of the calcium-sensing receptor (CaR) can attenuate parathyroid hyperplasia in rats with secondary HPT. The present study explores the effects of the calcimimetic cinacalcet HCl on parathyroid hyperplasia, apoptosis, and PTH secretion in a rat model of secondary HPT.


METHODS
Cinacalcet HCl was gavaged daily (1, 5, or 10 mg/kg) for 4 weeks starting 6 weeks post-5/6 nephrectomy. After dosing, hyperplasia was determined using parathyroid weight and proliferating cell nuclear antigen (PCNA) immunochemistry. Apoptosis was determined using in situ techniques. Serum PTH((1-34)) and blood chemistries were determined throughout the course of the study.


RESULTS
Administration of cinacalcet HCl (5 or 10 mg/kg) significantly reduced the number of PCNA-positive cells and decreased parathyroid weight compared with vehicle-treated 5/6 nephrectomized rats. There was no difference in apoptosis from cinacalcet HCl-treated or vehicle-treated animals. Serum PTH and blood ionized calcium levels decreased in cinacalcet HCl-treated animals compared with vehicle-treated controls.


CONCLUSIONS
The results confirm previous work demonstrating that calcimimetic agents attenuate the progression of parathyroid hyperplasia in subtotally nephrectomized rats, extending earlier observations to now include cinacalcet HCl. These results support a role for the CaR in regulating parathyroid cell proliferation. Therefore, cinacalcet HCl may represent a novel therapy for improving the management of secondary HPT.
Colloton
Matthew
M
Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, California 91320, USA.
Shatzen
Edward
E
Miller
Gerald
G
Stehman-Breen
Catherine
C
Wada
Michihito
M
Lacey
David
D
Martin
David
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000097:blood; D000069449:Cinacalcet; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006965:Hyperplasia; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D010280:Parathyroid Glands / Q000187:drug effects* / Q000473:pathology; D010281:Parathyroid Hormone / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
D009281:Naphthalenes; D010281:Parathyroid Hormone; D002118:Calcium; D000069449:Cinacalcet