Deletion of Irs2 causes reduced kidney size in mice: Role for inhibition of GSK3?

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 PKB/Akt2, hyperphosphorylation of GSK3 and concomitant accumulation of -catenin in Irs2^-/- kidney. Despite this, no significant upregulation of -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 -catenin and YAP levels failed to overcome this developmental defect. These data point to Irs2 as an important novel mediator of kidney size.