Growth hormone (GH)‐transgenic insulin‐like growth factor 1 (IGF1)‐deficient mice allow dissociation of excess GH and IGF1 effects on glomerular and tubular growth

Abstract

Growth hormone ( GH)‐transgenic mice with permanently elevated systemic levels of GH and insulin‐like growth factor 1 ( IGF1) reproducibly develop renal and glomerular hypertrophy and subsequent progressive glomerulosclerosis, finally leading to terminal renal failure. To dissociate IGF1‐dependent and ‐independent effects of GH excess on renal growth and lesion development in vivo, the kidneys of 75 days old IGF1‐deficient ( I ^−/− ) and of IGF1‐deficient GH‐transgenic mice ( I ^−/− /G), as well as of GH‐transgenic ( G) and nontransgenic wild‐type control mice ( I ^+/+ ) were examined by quantitative stereological and functional analyses. Both G and I ^−/− /G mice developed glomerular hypertrophy, hyperplasia of glomerular mesangial and endothelial cells, podocyte hypertrophy and foot process effacement, albuminuria, and glomerulosclerosis. However, I ^−/− /G mice exhibited less severe glomerular alterations, as compared to G mice. Compared to I ^+/+ mice, G mice exhibited renal hypertrophy with a significant increase in the number without a change in the size of proximal tubular epithelial ( PTE) cells. In contrast, I ^−/− /G mice did not display significant PTE cell hyperplasia, as compared to I ^−/− mice. These findings indicate that GH excess stimulates glomerular growth and induces lesions progressing to glomerulosclerosis in the absence of IGF1. In contrast, IGF1 represents an important mediator of GH‐dependent proximal tubular growth in GH‐transgenic mice.