GLOMERULAR LESIONS IN MICE TRANSGENIC FOR GROWTH HORMONE

转完整牛生长激素(BGH)的小鼠发育成 弥漫性肾小球硬化，类似于 发生在人类糖尿病中。相比之下，转基因小鼠的基因突变形式 在GH，G119K小鼠中，(第三螺旋突变)不发育肾脏 对链脲佐菌素引起的糖尿病肾病有抵抗力。 这些观察使我们假设生长激素的第三个螺旋 分子中含有一个结构域，它对 肾小球硬化。当我们将BGH小鼠与转基因小鼠杂交时 G119K突变，由此产生的后代有肾小球病变 与完整的BGH和突变的BGH的比例平行。此数据 证实生长激素在肾小球发育中的直接作用 损伤。支持这一假说的进一步证据在 小鼠，我们在其中放置了编码IGF-1 BP1的转基因。这些老鼠 循环中基本上没有游离的IGF-1。作为结果， 缺乏反馈调节循环中的生长激素水平相当高 抬高了。纯合子小鼠患上了一种严重的 肾小球硬化与生长激素小鼠相似。这些 观察证实，IGF-1可能不是一个重要的调节因子 生长激素所致疾病中的肾小球硬化。最后，IGF-1的缺乏 似乎损害了肾脏的生成，因为我们发现肾脏减少了10%到20% 在IGF BP1转基因小鼠的肾单位数量上，在它们的小鼠中， 转基因母亲所生的小鼠也是如此。这些数据表明 虽然IGF-1在肾脏的发育中起作用，但它不起作用 似乎与肾小球硬化有关。

Mice transgenic for an intact bovine growth hormone (bGH) develop a diffuse form of glomerulosclerosis which mimics the renal lesions that occur in human diabetes. In contrast, mice transgenic for a mutated form of GH, G119K mice, (mutated in the third helix) do not develop renal lesions and are resistant to steptozotocin-induced diabetic nephropathy. These observations led us to postulate that the third helix of the GH molecule contains a domain that is critical for the development of glomerulosclerosis. When we crossed bGH mice with mice transgenic for the G119K mutation, the resulting offspring had glomerular lesions which paralleled the ratio between the intact and mutant bGH. This data confirmed the direct role of GH in the development of the glomerular lesion. Further evidence in support of this hypothesis was obtained in mice, in which we placed a transgene coding for IGF-1 BP1. These mice have essentially no free IGF-1 in the circulation. As a result of the absence of feedback regulation the circulating GH levels are quite elevated. The homozygous mice developed a severe form of glomerulosclerosis resembling that found in the GH mice. These observations confirm that IGF-1 may not be a significant mediator of glomerulosclerosis in GH induced disease. Finally the lack of IGF-1 appeared to impair nephrogenesis, since we found a 10 to 20 % reduction in nephron number in the IGF BP1 transgenic mice, in their littermates, as well as in mice born of transgenic mothers. These data suggest that while IGF-1 plays a role in the development of the kidney, it does not seem to be involved in glomerulosclerosis.