Khamaisi Mogher, Søndergaard Morten, Segev Yael, Dagnaes-Hansen Frederik, Jensen Thomas G, Landau Danny, Raz Itamar, Flyvbjerg Allan
The Medical Research Laboratories, Clinical Institute and Medical Department M (Diabetes and Endocrinology), Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark.
Growth Horm IGF Res. 2007 Aug;17(4):279-87. doi: 10.1016/j.ghir.2007.01.018. Epub 2007 Mar 27.
Non-viral gene transfer was investigated as a potential modality for the treatment of growth hormone deficiency (GHD) using hypophysectomized (Hx) mice as a model. Hx mice were injected with a control plasmid or a plasmid containing the human (h) GH gene driven by a ubiquitin promoter, or left untreated. Treatment with the hGH gene has previously been shown to normalize longitudinal growth and serum insulin-like growth factor I (IGF-I). The present study was conducted to examine the renal/hepatic changes and gene/peptide expression of the GH/IGF-I axis in animals chronically expressing hGH. Following a single hydrodynamic administration of a plasmid DNA containing the hGH gene, a sustained elevation of the circulating hGH level was observed throughout the entire observation period, with a concomitant normalization of circulating IGF-I and IGF-binding protein 3 (IGFBP-3). In addition, longitudinal growth was corrected by normalizing tibia length, tail length, and body weight gain. Interestingly, kidney weights were only partly normalized, whereas kidney glomerular volume and liver weights were fully normalized. Kidney and liver IGF-I protein content was reduced in the Hx mice, but was normalized by hGH treatment. Kidney and liver GH receptor (GHR) mRNA levels were unchanged in the Hx mice, whereas the liver IGF-I mRNA level was reduced in the Hx mice, but was normalized by hGH treatment. We conclude that non-viral hGH gene transfer in Hx mice, which normalizes longitudinal growth and serum IGF-I levels, has differential effects on renal growth and glomerular volume. The potential effects of such excess glomerular growth induced by this intervention require further investigation.
以垂体切除（Hx）小鼠为模型，研究了非病毒基因转移作为治疗生长激素缺乏症（GHD）的一种潜在方式。给Hx小鼠注射对照质粒或含有由泛素启动子驱动的人（h）GH基因的质粒，或不进行处理。先前已证明用hGH基因治疗可使纵向生长和血清胰岛素样生长因子I（IGF-I）正常化。本研究旨在检查长期表达hGH的动物中GH/IGF-I轴的肾脏/肝脏变化以及基因/肽表达。在单次水动力注射含hGH基因的质粒DNA后，在整个观察期内均观察到循环hGH水平持续升高，同时循环IGF-I和IGF结合蛋白3（IGFBP-3）正常化。此外，通过使胫骨长度、尾巴长度和体重增加正常化来纠正纵向生长。有趣的是，肾脏重量仅部分正常化，而肾肾小球体积和肝脏重量完全正常化。Hx小鼠的肾脏和肝脏IGF-I蛋白含量降低，但通过hGH治疗使其正常化。Hx小鼠的肾脏和肝脏生长激素受体（GHR）mRNA水平未改变，而Hx小鼠的肝脏IGF-I mRNA水平降低，但通过hGH治疗使其正常化。我们得出结论，在Hx小鼠中进行非病毒hGH基因转移可使纵向生长和血清IGF-I水平正常化，但对肾脏生长和肾小球体积有不同影响。这种干预引起的肾小球过度生长的潜在影响需要进一步研究。
