Down-regulation of PTH-PTHrP receptor of heart in CRF: Role of [Ca2+]i

Abstract

The mRNA of PTH-PTHrP receptor in the kidney and liver of CRF rats is down-regulated. It is not known whether this is a generalized phenomenon and the signals that mediate such down-regulation are not evident. Excess PTH in CRF induces a rise in basal levels of cytosolic calcium ([Ca2+]i), and the high [Ca2+]i is implicated in the genesis of cell dysfunction in CRF. Therefore, it is reasonable to propose that the PTH-induced rise in [Ca2+]i provides a negative feedback control system for the down-regulation of the mRNA of the PTH-PTHrP in order to protect the cells from the harmful effects of progressive rise in blood levels of PTH in CRF. The heart contains the mRNA for this receptor and it is a target organ for PTH action. We examined whether the message of the PTH-PTHrP receptor is down-regulated in the heart of CRF animals and evaluated the role of [Ca2+]i in this process. The expression of the mRNA of the PTH-PTHrP was significantly reduced in the heart of CRF rats as compared to normal animals. Also, the CRF rats had elevated blood levels of PTH and high [Ca2+]i of cardiac myocytes. The parathyroidectomy of CRF rats prevented the rise in blood PTH levels and normalized [Ca2+]i of cardiac myocytes and returned the mRNA of their PTH-PTHrP receptor towards normal levels. The treatment of CRF rats with verapamil normalized [Ca2+]i of cardiac myocytes and returned the mRNA of their PTH-PTHrP receptor towards normal levels, despite marked elevation of blood levels of PTH. The data show that: (1) down-regulation of mRNA of PTH-PTHrP receptor occurs in heart of CRF rats; (2) this is due to the secondary hyperparathyroidism of CRF; and (3) one of the signals for this phenomenon is the PTH-induced rise in basal levels of [Ca2+]i. It is proposed that the latter may adversely affect the gene expression and/or increase the degradation of the mRNA of the PTH-PTHrP receptor.