Effect of pulsatile growth hormone administration to the growth-restricted fetal sheep on somatotrophic axis gene expression in fetal and placental tissues
Effect of pulsatile growth hormone administration to the growth-restricted fetal sheep on somatotrophic axis gene expression in fetal and placental tissues
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DOI：
10.1152/ajpendo.00045.2006
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发表时间：
2006-08-01
影响因子：
5.1
通讯作者：
Harding, J. E.
中科院分区：
文献类型：
--
作者：
Bloomfield, F. H.;van Zijl, P. L.;Harding, J. E.
我们之前已经报道过（Bauer MK，Breier BH，布卢姆菲尔德FH，詹森EC，Gluckman PD和Harding JE. J Endocrinol 177：83-92，2003），向宫内生长受限（IUGR）的绵羊胎儿慢性脉冲输注生长激素（GH）增加了胎儿循环IGF-I水平，而不增加胎儿生长。我们假设acortisol诱导的胎儿肝GH受体（GH-R）mRNA水平上调，继发性IGF-I mRNA水平和循环IGF-I水平增加，但I型IGF受体（IGF-IR）下调作为一种解释。因此，我们通过实时RT-PCR测量了IUGR胎儿（妊娠110- 116天子宫胎盘栓塞诱导）的胎儿和胎盘组织中生长激素轴基因的mRNA水平，这些胎儿从117-126天接受了GH（总剂量3.5 mg/天）或溶媒的脉冲式输注，对照胎儿（每组n=5）。在第127天（足月，145天）收集组织。胎儿皮质醇浓度显着增加IUGR胎儿。然而，在肝脏中，GH-R，而不是IGF-I或IGF-IR，mRNA水平在两个IUGR组中均降低。相反，在胎盘，生长激素受体，IGF-I，IGF-IR的表达增加IUGR车辆输注胎儿。GH输注进一步增加胎盘GH-R和IGF-IR，但取消IGF-I mRNA水平的增加。GH输注降低了肌肉中IGF-I的表达，增加了肾脏中GH-R的表达，但降低了IGF-IR的表达。IUGR增加肝脏IGFBP-1和胎盘IGFBP-2和-3 mRNA水平，GH输注没有进一步的影响。总之，IUGR胎儿循环皮质醇浓度的适度增加并没有增加肝脏GH-R mRNA的表达，因此，不能解释我们在GH输注中发现的循环IGF-I水平的增加，这可能是由于清除率降低而不是产量增加。我们证明了IUGR胎儿生长激素轴的组织特异性调节，以及GH灌注胎儿中GH-R和IGF-I基因表达之间的不连续性，这不能用磷酸化STAT 5 b的改变来解释。
We have previously reported (Bauer MK, Breier BH, Bloomfield FH, Jensen EC, Gluckman PD, and Harding JE. J Endocrinol 177: 83-92, 2003) that a chronic pulsatile infusion of growth hormone (GH) to intrauterine growth-restricted ( IUGR) ovine fetuses increased fetal circulating IGF-I levels without increasing fetal growth. We hypothesized acortisol-induced upregulation of fetal hepatic GH receptor (GH-R) mRNA levels, secondary increases in IGF-I mRNA levels, and circulating IGF-I levels, but a downregulation of the type I IGF receptor (IGF-IR) as an explanation. We, therefore, measured mRNA levels of genes of the somatotrophic axis by real-time RT-PCR in fetal and placental tissues of fetuses with IUGR (induced by uteroplacental embolization from 110- to 116-days gestation) that received either a pulsatile infusion of GH (total dose 3.5 mg/day) or vehicle from 117-126 days and in control fetuses (n=5 per group). Tissues were collected at 127 days ( term, 145 days). Fetal cortisol concentrations were significantly increased in IUGR fetuses. However, in liver, GH-R, but not IGF-I or IGF-IR, mRNA levels were decreased in both IUGR groups. In contrast, in placenta, GH-R, IGF-I, and IGF-IR expression were increased in IUGR vehicle-infused fetuses. GH infusion further increased placental GH-R and IGF-IR, but abolished the increase in IGF-I mRNA levels. GH infusion reduced IGF-I expression in muscle and increased GH-R but decreased IGF-IR expression in kidney. IUGR increased hepatic IGF-binding protein (IGFBP)-1 and placental IGFBP-2 and -3 mRNA levels with no further effect of GH infusion. In conclusion, the modest increases in circulating cortisol concentrations in IUGR fetuses did not increase hepatic GH-R mRNA expression and, therefore, do not explain the increased circulating IGF-I levels that we found with GH infusion, which are likely due to reduced clearance rather than increased production. We demonstrate tissue-specific regulation of the somatotrophic axis in IUGR fetuses and a discontinuity between GH-R and IGF-I gene expression in GH-infused fetuses that is not explained by alterations in phosphorylated STAT5b.