We have shown that mice transgenic for growth hormone develop a rapidly progressive glomerulosclerosis. Mice transgenic for GH molecules containing mutations have also been examined in order to dissociate the domains of GH that may specifically code for genes responsible for glomerulosclerosis from those coding for body mass increase. We found an upregulation of mRNA for extracellular matrix components in the glomeruli of the GH animals by competitive PCR of isolated microdissected glomeruli. This upregulation persisted late in the course of the disease. We have started exploring therapeutic manipulations using angiotensin converting enzyme inhibitors (ACEI) and non-anticoagulant heparin. The effects of treatment were followed by morphology, and competitive PCR for type IV collagen, type I collagen, smooth muscle actin, and laminin B1 mRNAs. The course of the glomerular lesions was unaltered following ACEI therapy and there appeared to be a worsening of vascular lesions, presumably due to a local increase of renin. In addition, there was no decrease in mRNAs coding for any of the genes listed above. In contrast, the lesions were reduced by light microscopy and the mRNA coding for the 92kD matrix metalloproteinase complex was increased after two weeks of heparin treatment. The nature of the heparin effect is currently being investigated in further detail, since this molecule or other related species, could be used in the treatment of intractable progressive human glomerulosclerosis. Mice transgenic for a mutated growth hormone (M11) exhibit a much slower rate of progression than the mice described above. The levels of glomerular ECM mRNAs, measured early at 3 months of age, are intermediate between those of the GH mice and normal controls. These data suggest that fast and slow progressors can be identified prior to the appearance of histologic lesions, which had heretofore had been the sole means to determine the presence of glomerulosclerosis.
