Deletion of Irs2 Causes Reduced Kidney Size in Mice: Role for Inhibition of GSK3β?

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Deletion of Irs2 Causes Reduced Kidney Size in Mice: Role for Inhibition of GSK3β?

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Title: Deletion of Irs2 Causes Reduced Kidney Size in Mice: Role for Inhibition of GSK3β?
Author: Carew, Rosemarie M; Goldschmeding, Roel; Martin, Finian; Brazil, Derek P; Sadagurski, Marianna; White, Morris Francis

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Citation: Carew, Rosemarie M., Marianna Sadagurski, Roel Goldschmeding, Finian Martin, Morris F. White, and Derek P. Brazil. 2010. Deletion of Irs2 causes reduced kidney size in mice: role for inhibition of GSK3β? BMC Developmental Biology 10: 73.
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Abstract: Background: Male \(Irs2^{-/-}\) mice develop fatal type 2 diabetes at 13-14 weeks. Defects in neuronal proliferation, pituitary development and photoreceptor cell survival manifest in \(Irs2^{-/-}\) mice. We identify retarded renal growth in male and female \(Irs2^{-/-}\) mice, independent of diabetes. Results: Kidney size and kidney:body weight ratio were reduced by approximately 20% in \(Irs2^{-/-}\) mice at postnatal day 5 and was maintained in maturity. Reduced glomerular number but similar glomerular density was detected in \(Irs2^{-/-}\) kidney compared to wild-type, suggesting intact global kidney structure. Analysis of insulin signalling revealed renal-specific upregulation of PKBβ/Akt2, hyperphosphorylation of GSK3β and concomitant accumulation of β-catenin in \(Irs2^{-/-}\) kidney. Despite this, no significant upregulation of β-catenin targets was detected. Kidney-specific increases in Yes-associated protein (YAP), a key driver of organ size were also detected in the absence of Irs2. YAP phosphorylation on its inhibitory site Ser127 was also increased, with no change in the levels of YAP-regulated genes, suggesting that overall YAP activity was not increased in \(Irs2^{-/-}\) kidney. Conclusions: In summary, deletion of Irs2 causes reduced kidney size early in mouse development. Compensatory mechanisms such as increased β-catenin and YAP levels failed to overcome this developmental defect. These data point to Irs2 as an important novel mediator of kidney size.
Published Version: doi:10.1186/1471-213X-10-73
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