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.
