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Postnatally Elevated Levels of Insulin-Like Growth Factor (IGF)-II Fail to Rescue the Dwarfism of IGF-I-Deficient Mice except Kidney Weight

Institute of Molecular Animal Breeding and Biotechnology (C.M., M.R.S., I.R.-M., A.B., E.W.), Gene Center, Institute of Animal Physiology (R.G.E.), Veterinary Faculty, University of Munich, D-81377 Munich, Germany; Department of Pediatric Endocrinology (M.W.E.), Children’s Hospital, University of Tuebingen, D-72074 Tuebingen, Germany; Department of Endocrinology (C.C.-H.), William Harvey Research Institute, University of London, London E1 4NS, United Kingdom; and Research Unit Genetics and Biometry (A.H.), Research Institute for the Biology of Farm Animals, D-18196 Dummerstorf, Germany

Address all correspondence and requests for reprints to: Professor Dr. Eckhard Wolf, Institute of Molecular Animal Breeding and Biotechnology, Gene Center, University of Munich, Feodor-Lynen-Str. 25, D-81377 Munich, Germany. E-mail: ewolf{at}lmb.uni-muenchen.de.

This study tested whether elevated levels of IGF-II in the postnatal period can rescue the dwarfism in IGF-I-deficient mice. Heterozygous Igf1 mutant mice [I^+/– II^wt] were crossed with heterozygous Igf1 mutant, phosphoenolpyruvate carboxykinase promoter IGF-II transgenic mice [I^+/– II^tg], and [I^+/+ II^wt], [I^+/+ II^tg], [I^–/– II^wt], and [I^–/– II^tg] offspring were investigated. IGF-II levels were 11- and 6-fold higher in male and female [I^–/– II^tg] vs. [I^–/– II^wt] animals. Western ligand blot analysis revealed markedly reduced activities of 30- and 32-kDa IGF binding proteins (IGFBPs) (most likely IGFBP-1 and IGFBP-2) and the 39- to 43-kDa IGFBP-3 double band in serum from IGF-I-deficient mice. These binding proteins were partially restored by overexpression of IGF-II. Analysis of weight data from the early postnatal period until d 60 showed that, in the absence of IGF-I, elevated levels of IGF-II have no effect on body weight gain. A detailed analysis of body proportions, bone parameters, and organ weights of 60-d-old mice also failed to show effects of IGF-II with one important exception: in Igf1 mutant and also Igf1 intact male mice, IGF-II overexpression significantly increased absolute (+32.4 and +28.6%; P < 0.01) and relative kidney weights (+29.0 and +22.4%; P < 0.001). These changes in kidney weight were associated with reduced phosphorylation of p38 MAPK. In summary, our genetic model shows that substantial amounts of IGF-II in the circulation do not rescue the postnatal growth deficit of IGF-I-deficient mice but increase absolute and relative kidney weights of normal and IGF-I-deficient male mice, suggesting a gender-specific role of IGF-II for kidney growth.

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