Differential in vivo regulation of the pituitary growth hormone-releasing hormone (GHRH) receptor by GHRH in young and aged rats
Differential in vivo regulation of the pituitary growth hormone-releasing hormone (GHRH) receptor by GHRH in young and aged rats
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DOI：
10.1210/en.140.6.2836
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发表时间：
1999-06-01
期刊：
影响因子：
4.8
通讯作者：
Gaudreau, P
中科院分区：
文献类型：
--
作者：
Girard, N;Boulanger, L;Gaudreau, P
在衰老过程中，垂体生长激素释放激素 (GHRH) 受体 (GHRH-R) 结合位点的改变被认为是导致生长激素对 GHRH 反应性丧失的起始因素之一。在衰老过程中，功能性 GHRH-R 的特性和/或浓度可能会发生变化，并降低生长激素轴对 GHRH 的敏感性。由于长期暴露于 GHRH 可以使衰老的生长激素细胞重新变得敏感，因此需要更好地了解其对生长激素轴调节的影响，特别是在 GHRH-R 水平上。 2 个月和 18 个月大的雄性 Sprague Dawley 大鼠每天皮下注射 0.5 或 1.0 mg/kg BW 人 GHRH(1-29)NH2 或盐水，治疗 14 天。在 2 个月大的大鼠中，用 0.5 mg/kg GHRH 治疗可使垂体 GHRH-R 高亲和力结合位点的数量增加 2 倍（P < 0.05），下丘脑生长抑素（SRIF）含量增加 45%（P < 0.05）。它不影响下丘脑 GHRH 含量、血清总胰岛素样生长因子 I (IGF-I) 或体重增加。与0.5 mg/kg BW处理的大鼠相比，1.0 mg/kg GHRH处理使垂体GHRH-R高亲和力结合位点数量减少2.4倍（P < 0.05），使下丘脑SRIF含量增加45%（P < 0.05），但不影响GHRH含量。它还使 IGF-I 的循环水平降低了 13%（P < 0.05），并使生长速度减慢了 17%（P < 0.05）。在 18 个月大的大鼠中，用 0.5 mg/kg GHRH 治疗 14 天不足以恢复垂体 GHRH 结合参数。然而，用 1.0 mg/kg GHRH 治疗可将 GHRH 结合位点的高亲和力类别和低亲和力类别的亲和力恢复到与 2 个月大的大鼠中发现的值相似的值。高亲和力类别和低亲和力类别的位点的结合能力分别增加了 1.8 倍和 3 倍，但仅低亲和力位点才达到显着性（P < 0.05）。这些变化与 2.5-kb GHRH-R 信使 RNA 转录水平的正常化有关，在老龄大鼠中该转录水平下降了 31%（P < 0.05），并且与 4-kb GHRH-R 信使 RNA 转录水平的增加趋势有关，在 18 个月大的大鼠中该转录水平已经增加了 49%（P < 0.05）。还观察到血清 IGF-I 水平正常化，18 个月大的对照大鼠中血清 IGF-I 水平降低了 11%（P < 0.01）。未检测到对体重或下丘脑 SRIF 和 GHRH 含量的治疗效果。我们得出的结论是，14 天的 GHRH 给药会在垂体水平（可能还有下丘脑水平）诱导 GHRH-R 介导的差异性调节（作为年龄的函数）。
In aging, alterations of pituitary GH-releasing hormone (GHRH) receptor (GHRH-R)-binding sites have been proposed as one of the initiating factors contributing to the loss of somatotroph responsiveness to GHRH. Changes in the characteristics and/or concentration of the functional GHRH-R could take place in the course of aging and reduce the sensitivity of the somatotroph axis to GHRH. Because chronic exposure to GHRH has been proposed to resensitize aged somatotroph cells, better knowledge of its effects on the regulation of the somatotroph axis is required, particularly at the level of GHRH-R. Two- and 18-month-old male Sprague Dawley rats were treated for 14 days with a daily sc injection of 0.5 or 1.0 mg/kg BW human GHRH(1-29)NH2 or saline. In 2-month-old rats, treatment with 0.5 mg/kg GHRH increased the number of high affinity pituitary GHRH-R-binding sites by 2-fold (P < 0.05) and hypothalamic somatostatin (SRIF) content by 45% (P < 0.05). It did not affect hypothalamic GHRH content, serum total insulin-like growth factor I (IGF-I), or body weight gain. Treatment with 1.0 mg/kg GHRH decreased the number of high affinity pituitary GHRH-R-binding sites by 2.4-fold compared with that in rats treated with 0.5 mg/kg BW (P < 0.05) and increased hypothalamic SRIF content by 45% (P < 0.05), but did not affect GHRH content. It also decreased circulating levels of IGF-I by 13% (P < 0.05) and slowed the growth rate by 17% (P < 0.05). In 18-month-old rats, treatment with 0.5 mg/kg GHRH for 14 days was not sufficient to rejuvenate pituitary GHRH binding parameters. However, treatment with 1.0 mg/kg GHRH restored the affinities of high and low affinity classes of GHRH-binding sites to values similar to those found in 2-month-old rats. Binding capacities of the high and low affinity classes of sites were increased by 1.8- and 3-fold, respectively, although significance was only reached for the low affinity site (P < 0.05). These changes were associated with a normalization of the level of 2.5-kb GHRH-R messenger RNA transcript, which was decreased by 31% in aging rats (P < 0.05), and by a trend for an increase in the 4-kb GHRH-R messenger RNA transcript, which was already increased by 49% in 18-month-old rats (P < 0.05). A normalization of serum IGF-I levels, which were decreased by 11% in 18-month-old control rats (P < 0.01), was also observed. No treatment effect was detected on body weight or hypothalamic SRIF and GHRH contents. We conclude that a 14-day administration of GHRH induces a differential GHRH-R-mediated regulation at the level of the pituitary and probably the hypothalamus as a function of age.