The role of the type I insulin-like growth factor receptor (IGF-IR) in glomerular integrity

Insulin-like growth factors (IGFs) have been implicated in normal mammalian kidney development. To confirm a role for the IGF system in podocyte and glomerular integrity, we generated a transgenic mouse that expresses a dominant-negative type 1 IGF receptor (IGF-IR) and determined the structural and functional consequences. Using a 4.25kb fragment of the murine nephrin promoter, the dominant-negative construct was expressed exclusively in the kidney, confirmed by Southern blot and RT-PCR analysis. IGF-Ir486(FLAGstop) protein localized specifically to the glomerular podocyte based on FLAG immunohistochemistry and on co-localization with nephrin and podocin. Wild type and transgenic glomeruli expressed both the alpha- and beta-subunits of the endogenous IGF-IR, with normal expression of both nephrin and podocin. Although the animals were viable and phenotypically normal, histological analysis of the kidneys revealed abnormal and small glomeruli with dilated glomerular capillaries and condensed podocyte nuclei, while ultra-structural examination revealed diffuse but segmental podocyte foot process broadening, fusion, and effacement. Explanted glomeruli from transgenic animals demonstrated a significant inhibition of podocyte cell outgrowth when compared to controls. These studies suggest that IGF signaling is essential for maintaining the integrity of the podocyte and that alterations of IGF signaling may play a role in progressive glomerular disease.