Structure and Function of Integrins in the Kidney

点击翻译按钮获取中文摘要

Abstract The stoichiometric cis association of the tetraspanin CD151 with podocyte integrin α3β1 is essential for stabilizing α3β1 in an active ligand-binding conformation, thus maintaining the integrity of the glomerular filtration barrier (GFB). Other studies also show that activation of αvβ3 in podocytes by inflammatory mediators, growth factors or mechanical/shear stress plays a critical role in disrupting the GFB. Taken together, these data suggest that α3β1 and αvβ3 play opposing roles in regulating GFB homeostasis, but the biochemical and structural basis of this functional antagonism in disease is unknown and how the glomerulus responds to injury in the complete absence or inactivation of podocyte αvβ3 remains to be clarified. In preliminary studies, we show that αvβ3 ectodomain binds CD151 with similar EC50 to α3β1, that this interaction requires the active conformation of αvβ3 and is promoted by the αvβ3 inhibitors used in prior studies acting as partial agonists. These data lead us to propose and test the hypothesis that activation of αvβ3 in disease states sequesters CD151 away from binding to α3β1, thus impairing optimal α3β1 function and disrupting the GFB. In other preliminary studies, we demonstrate the feasibility of obtaining a cryo-EM structure of an integrin in an inactive conformation in complex with a tetraspanin, providing the feasibility for determining the structural basis of the active integrin conformation that forms the complex with CD151. We have also generated mice with podocyte specific deletion of αv and developed a novel class of αvβ3 inhibitors that are not partial agonists and that prevent rather than promote αvβ3/CD151 association, which will also allow us to examine the glomerular response to injury when αvβ3 is inactivated genetically or pharmacologically in rodent models of proteinuric kidney disease.