We have shown that mice transgenic for growth hormone develop a rapidly progressive glomerulosclerosis. The lesions resemble those occurring in Diabetes mellitus. 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 (ACE I) 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 the former 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 mRNAs coding for several extracellular matrix components decreased substantially following 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 proposed in the treatment of intractable progressive human glomerulosclerosis for which there is presently no effective therapy.
