GLOMERULAR LESIONS IN MICE TRANSGENIC FOR GROWTH HORMONE

生长激素转基因小鼠的肾小球损伤

• 批准号: 6161981
• 负责人: L J STRIKER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6161981
• 关键词: cellular pathology; collagen; diabetic nephropathy; disease /disorder model; gene expression; genetically modified animals; glomerulosclerosis; hormone receptor; hormone regulation /control mechanism; immunofluorescence technique; laboratory mouse; polymerase chain reaction; receptor binding; renal glomerulus; somatotropin; streptozotocin

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.

完整牛生长激素（bGH）转基因小鼠发育为 弥漫性肾小球硬化，类似肾脏病变， 发生在人类糖尿病中。相反，转基因小鼠的突变形式， GH，G119 K小鼠（第三螺旋突变）不发生肾性 并且对链脲佐菌素诱导的糖尿病肾病具有抗性。 这些观察使我们假设GH的第三个螺旋 分子包含一个对于开发至关重要的结构域 肾小球硬化 当我们将bGH小鼠与转基因小鼠杂交时， G119 K突变，产生的后代有肾小球病变， 计算完整和突变bGH之间的比率。 该数据 证实了GH在肾小球发育中的直接作用。 损伤。 支持这一假设的进一步证据是在 小鼠，其中我们放置了编码IGF-1 BP 1的转基因。 这些小鼠 血液循环中基本上没有游离的IGF-1。 的结果 缺乏反馈调节，循环GH水平相当 升高。 纯合子小鼠发展出一种严重的 肾小球硬化症，类似于GH小鼠中发现的肾小球硬化症。 这些 观察证实，IGF-1可能不是一个重要的调解人， GH诱导的肾小球硬化症。 最后，缺乏IGF-1 似乎会损害肾发生，因为我们发现， 在同窝出生的IGF BP 1转基因小鼠中， 以及转基因母亲所生的小鼠。 这些数据表明 虽然IGF-1在肾脏的发育中起作用，但它不 似乎与肾小球硬化症有关