Effects of dietary-induced hyperparathyroidism on the parathyroid hormone-receptor-adenylate cyclase system of canine kidney. Evidence for postreceptor mechanism of desensitization.
Effects of dietary-induced hyperparathyroidism on the parathyroid hormone-receptor-adenylate cyclase system of canine kidney. Evidence for postreceptor mechanism of desensitization.
复制标题
饮食引起的甲状旁腺功能亢进症对犬肾甲状旁腺激素-受体-腺苷酸环化酶系统的影响。
DOI：
10.1172/jci110990
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发表时间：
1983
期刊：
影响因子：
--
通讯作者：
Martin,KJ
中科院分区：
文献类型：
--
作者：
Tamayo,J;Bellorin-Font,E;Martin,KJ
本研究旨在探讨犬肾皮质内源性甲状旁腺激素(PTH)慢性轻度升高对PTH受体-腺苷环化酶系统的影响。用低钙高磷饲料喂养正常犬6~9wk，诱发正常犬甲状旁腺功能亢进症。这一动作导致血浆中羧基末端免疫反应性甲状旁腺素水平增加两到三倍。甲状旁腺功能亢进症的程度与肾功能正常的甲状旁腺功能亢进症患者相似。饲养6~9wk后处死动物，制备肾皮质基底膜，用于体外研究PTH受体-腺苷环化酶系统。饮食甲状旁腺功能亢进导致甲状旁腺激素反应性腺苷环化酶失敏(甲状旁腺功能亢进症动物每30分钟Vmax为3,648+/-654 pmol环(C)AMP/mg蛋白，而正常对照组为5,303+/-348)。Kact(半峰酶激活所需的甲状旁腺素浓度)没有变化。然而，两组动物的甲状旁腺素受体结合(以125I[Nle8，Nle18，Tyr34]bpth(1-34)NH2为放射性配基)无差异。因此，饮食甲状旁腺机能亢进症导致甲状旁腺素受体-腺苷环化酶系统的解偶联。鸟苷在体外不能纠正这种缺陷，鸟苷对甲状旁腺激素结合和酶活性的影响是正常的。在甲状旁腺功能亢进组，NaF刺激的酶活性降低(每30分钟8,285+/-607pmolcAMP/mg蛋白，对照组为10,851+/-247)。这些结果表明，犬肾脏PTH反应性腺苷环化酶系统的脱敏是由于受体后缺陷所致，这种缺陷表现为NaF的激活，但不能被鸟苷纠正，导致PTH-受体腺苷环化酶偶联异常。
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 Kact (concentration of PTH required for half-maximal enzyme activation) was unchanged. However, PTH receptor binding (125I-norleucyl8-norleucyl18-tyrosinyl34, 125I[Nle8, Nle18, 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 by guanyl nucleotides in vitro, and the effects of guanyl nucleotides on PTH binding and enzyme activation appeared normal. NaF-stimulated enzyme activity was reduced in the hyperparathyroid animals (8,285 +/- 607 pmol cAMP/mg protein per 30 min vs. 10,851 +/- 247 in controls). These data indicate that desensitization of the PTH-responsive adenylate cyclase system of canine kidney as a result of mild chronic elevations of endogenous PTH is due to a postreceptor defect, demonstrable by NaF activation, not corrected by guanyl nucleotides, leading to abnormal PTH-receptor adenylate cyclase coupling.