title: 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.
authors.affiliation: Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University Muenchen, Munich, Germany blutke@patho.vetmed.uni-muenchen.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Blutke
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Centre Ludwig-Maximilians-University Muenchen, Munich, Germany.
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Schneider
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Centre Ludwig-Maximilians-University Muenchen, Munich, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University Muenchen, Munich, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Wanke
mesh_terms: D000818:Animals; D005260:Female; D013006:Growth Hormone / Q000172:deficiency* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000254:growth & development* / Q000378:metabolism* / Q000648:ultrastructure; D007684:Kidney Tubules / Q000254:growth & development* / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone
keywords: Glomerulosclerosis; kidney; quantitative stereology