Effects of dietary-induced hyperparathyroidism on the parathyroid hormone-receptor-adenylate cyclase system of canine kidney. Evidence for postreceptor mechanism of desensitization.

Abstract

A B S T R A C T The present studies were designed to examine the consequences of chronic mild elevations of endogenous parathyroid hormone (PTH) in vivo on the PTH receptor-adenylate cyclase system of canine kidney cortex. Hyperparathyroidism was induced in normal dogs by feeding a diet low in calcium, high in phosphorus to the animals for a period of 6-9 wk. This maneuver resulted in a two to threefold increase in the plasma levels of carboxy-terminal immunoreactive PTH. This degree of hyperparathyroidism is similar to that seen in patients with hyperparathyroidism and normal renal function. After 6-9 wk on the diet the animals were killed and basolateral renal cortical membranes prepared for the study of the PTH receptor-adenylate cyclase system in vitro. The dietary hyperparathyroidism resulted in desensitization of the PTH-responsive adenylate cyclase (Vmax 3,648±654 pmol cyclic (c)AMP/mg protein per 30 min in hyperparathyroid animals vs. 5,303±348 in normal controls). The Ka.t (concentration of PTH required for half-maximal enzyme activation) was unchanged. However, PTH receptor binding '251[Nle , Nle'8, Tyr34] bPTH (1-34) NH2 as radioligand) was not different in the two groups of animals. Thus, dietary hyperparathyroidism resulted in an uncoupling of the PTH receptor-adenylate cyclase system. This defect was not corrected

Desensitization to parathyroid hormone in renal cells from aged rats is associated with alterations in G-protein activity.

“…PTH-mediated refractoriness of the cAMP system was reported in a variety of experimental models, including prolonged (8-20 h) infusion of massive quantities of exogenous PTH (30)(31)(32), feeding animals a low Ca or vitamin D-deficient diet (15,33,34), and pre-treatment ofcultured chick renal and bone cells with the hormone (16,35). The general conclusion from these studies was that elevating circulating levels of PTH or increasing the concentration ofthe hormone in the medium down-regulated PTH-sensitive adenylate cyclase.…”

Effect of renal function on renal responsiveness to parathyroid hormone in primary hyperparathyroidism and chronic renal failure

“…A factor likely to play an important role in the renal resistance to hormonal action is the high endogenous PTH concentration itself, as we have previously suggested to occur in normal subjects infused with bovine PTH [ 11 and in the secondary hyperparathyroidism of vitamin-D deficiency [2]. Recent animal studies have suggested how high endogenous PTH concentrations may result in reduced responsiveness to the hormone by residual occupancy of receptors [20], by a reduction in receptor number [21,22] or by uncoupling of the receptorladenylate cyclase complex [23]. The fact that these animal studies have produced conflicting evidence for the mechanism of renal resistance to PTH emphasizes the need to define the resistance phenomenon as it occurs in man as far as it is possible in studies such as these described here.…”

Down-regulation of the PTH/PTHrP receptor in uremia

“…It has been suggested that these four factors are important in the occurrence of low calcium and calcitriol plasma levels and the subsequent development of secondary hyperparathyroidism. Such a phenomenon, known as desensitization, has been described for PTH in many experimental models, including cultured renal cells, bone tumor cells [12][13][14], vitamin D-deficient humans and animals [15J, aged animals [16], and dietary-induced hyperparathyroidism [17]. In a first of two experiments, we found a decrease of the level of the steady-state PTH-R mRNA in the kidney of uremic rats (5/6 nephrectomy) and a diminished PTH-sensitive adenylate cyclase activity [11].…”