Development of parathyroid gland hyperplasia without uremia: role of dietary calcium and phosphate.
Background. Many experimental studies have demonstrated that parathyroid cell proliferation is induced by uremia and further aggravated by hypocalcemia, phosphorus retention and vitamin D deficiency. However, these factors may also promote parathyroid growth without uremia. In the present study, we examined the onset and progression of parathyroid hyperplasia regardless of the uremic setting, a situation that might occur soon during the early renal disease. Thus, the novelty of this work resides in the close examination of the time course for the expected changes in proliferation rates and their association with parathyroid hormone (PTH) release in normal rats under the physiological demands of a high-phosphate diet (HPD) or a low-calcium diet (LCD). Methods. We evaluated the functional response of the parathyroid glands in normal rats to different physiological demands an HPD 0.6% Ca, 1.2% P) and LCD 0.2% Ca, 0.6% P) and compared it with that of uremic rats. Furthermore, we also evaluated the time course for the reversal of high-P and low-Ca-induced parathyroid cell growth and PTH upon normalization of dietary Ca and P intake (0.6% Ca, 0.6% P). Proliferation was measured by flow cytometry and calcium receptor (CaR) and vitamin D receptor (VDR) expression were assessed by qRT-PCR. Results. The pattern in the development of parathyroid hyperplasia by the two dietary models was different. The HPD produced a stronger stimulus than the number of proliferating cells doubled after only 1 day, while the LCD required 5 days to induce an increase; the elevated calcitriol might be a mitigating factor. The increase in cell proliferation was accompanied by a transient down-regulation of VDR expression (higher in the HPD); the expression of CaR was not affected by either diet. Cell proliferation and VDR mRNA levels were restored to control values by Day 15; it is as though the gland had attained a sufficient level of hyperplasia to respond to the PTH challenge. Compared to normal rats, the response of uremic rats to the HPD showed sustained and much higher rates of PTH secretion and cell proliferation and sustained down-regulation of both VDR mRNA and CaR mRNA. Finally, the recovery from the HPD or LCD to a control diet resulted in a rapid restoration of PTH values (1 to 2 days), but the reduction in cell proliferation was delayed (3 to 5 days). Conclusions. Regardless of uremia, a physiological demand to increase the PTH secretion driven either by a high P or a low Ca intake is able to induce a different pattern of parathyroid hyperplasia, which might be aggravated by the down-regulation of VDR expression. The recovery from the HPD or LCD to a control diet results in a more rapid reduction in PTH than in cell proliferation.
Canalejo
Antonio
A
Department of Environmental Biology and Public Health, University of Huelva, Huelva, Spain.
Canalejo
Rocio
R
Rodriguez
M Encarnacion
ME
Martinez-Moreno
Julio M
JM
Felsenfeld
Arnold J
AJ
Rodríguez
Mariano
M
Almaden
Yolanda
Y
D000818:Animals; D015153:Blotting, Western; D002136:Calcium, Dietary / Q000008:administration & dosage* / Q000494:pharmacology; D049109:Cell Proliferation; D006965:Hyperplasia; D008297:Male; D010280:Parathyroid Glands / Q000378:metabolism / Q000473:pathology*; D010281:Parathyroid Hormone / Q000378:metabolism*; D016226:Phosphorus, Dietary / Q000008:administration & dosage* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014511:Uremia / Q000378:metabolism / Q000473:pathology*
D002136:Calcium, Dietary; D010281:Parathyroid Hormone; D016226:Phosphorus, Dietary; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing