IMPAIRED AGONIST-INDUCED CALCIUM SIGNALING IN HEPATOCYTES FROM CHRONIC-RENAL-FAILURE RATS

Some hormones exert their action by inducing a rise in cytosolic calcium [Ca2+]i (calcium signal), and therefore, a blunting in hormone-induced calcium signal would engender resistance to the action of the hormone. Chronic renal failure (CRF) is associated with resistance to the action of a variety of hormones, a rise in [Ca2+]i and decrease in the amount of mRNA of one hormone receptor, the PTH-PTHrP receptor. We examined the calcium-signal induced by PTH, angiotensin II, vasopressin and glucagon in hepatocytes from CRF animals, evaluated the effect of the basal level [Ca2+]i on the calcium signal and explored the effect of [Ca2+]i on the mRNA of the receptors of these agonists. Hepatocytes from CRF rats have elevated basal levels of [Ca2+]i and display significantly reduced calcium signals induced by all these hormones, while the calcium signals were normal in PTX-CRF animals and those treated with verapamil both of which have normal levels of [Ca2+]i despite CRF. The calcium signals induced by dibutyryl cyclic AMP and G protein activator (GTP gamma S) were normal in hepatocytes from CRF animals despite the high levels of [Ca2+]i. Northern blotting experiments revealed that the levels of the mRNA of the receptors of PTH-PTHrP, angiotensin II and vasopressin were significantly reduced in hepatocytes from CRF animals but PTX-CRF rats and those treated with verapamil had either significantly greater or even normal amounts of the mRNA of these receptors. The results show that: (1) in CRF there is a reduction in the levels of the mRNA of hormone receptors which would likely lead to decreased production of the receptors protein, that is, down-regulation of receptors; (2) the elevation in [Ca2+]i in CRF plays an important role in this phenomenon; (3) the hepatocyte G protein-adenylate cyclase-cAMP pathway, which is important in mediating the calcium signals of many hormones, is not impaired in CRF; and (4) the reduction in the calcium signal induced by hormones is most likely due to down-regulation of the hormone receptors and may not be affected by the levels of [Ca2+]i per se.