Failure of high doses of calcitriol and hypercalcaemia to induce apoptosis in hyperplastic parathyroid glands of azotaemic rats.
BACKGROUND
Whether calcitriol administration, which is used to treat secondary hyperparathyroidism in dialysis patients, induces regression of parathyroid-gland hyperplasia remains a subject of interest and debate. If regression of the parathyroid gland were to occur, the presumed mechanism would be apoptosis. However, information on whether high doses of calcitriol can induce apoptosis of parathyroid cells in hyperplastic parathyroid glands is lacking. Consequently, high doses of calcitriol were given to azotaemic rats and the parathyroid glands were evaluated for apoptosis.


METHODS
Rats were either sham-operated (two groups) or underwent a two-stage 5/6 nephrectomy (three groups). For the first 4 weeks, all rats were given a high (1.2%) phosphorus (P) diet to stimulate parathyroid gland growth and then were changed to a normal (0.6%) P diet for 2 weeks. At week 7, three of the five groups were given high doses of calcitriol (500 pmol/100 g body weight) intraperitoneally every 24 h during 72 h before sacrifice. The five groups during week 7 were: (i) normal renal function (NRF)+0.6% P diet; (ii) NRF+0.6% P+calcitriol; (iii) renal failure (RF)+0.6% P; (iv) RF+1.2% P+calcitriol; and (v) RF+0.6% P+calcitriol. Parathyroid glands were removed at sacrifice and the TUNEL stain was performed to detect apoptosis.


RESULTS
At sacrifice, the respective serum calcium values in calcitriol-treated groups (groups 2, 4, and 5) were 15.52+/-0.26, 13.41+/-0.39 and 15.12+/-0.32 mg/dl. In group 3, PTH was 178+/-42 pg/ml, but in calcitriol-treated groups, PTH values were suppressed, 8+/-1 (group 2), 12+/-2 (group 4), and 7+/-1 pg/ml (group 5). Despite, the severe hypercalcaemia and marked PTH suppression in calcitriol-treated groups, the percentage of apoptotic cells in the parathyroid glands was very low (range 0.08+/-0.04 to 0.25+/-0.20%) and not different among the five groups.


CONCLUSIONS
We found no evidence in hyperplastic parathyroid glands that apoptosis could be induced in azotaemic rats by the combination of high doses of calcitriol and severe hypercalcaemia despite the marked reduction in PTH levels that was observed.
Jara
A
A
Department of Nephrology, Pontificia Universidad Católica de Chile, Santiago, Chile.
González
S
S
Felsenfeld
A J
AJ
Chacón
C
C
Valdivieso
A
A
Jalil
R
R
Chuaqui
B
B
D000818:Animals; D017209:Apoptosis; D002117:Calcitriol / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D006934:Hypercalcemia / Q000503:physiopathology*; D006965:Hyperplasia; D020287:In Situ Nick-End Labeling; D008297:Male; D010280:Parathyroid Glands / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014511:Uremia / Q000473:pathology / Q000503:physiopathology*
D002120:Calcium Channel Agonists; D002117:Calcitriol