Structure and Function of Integrins in the Kidney

Massachusetts General Hospital, Boston MA

Investigators

Linked publications, trials & patents

Abstract

Abstract The stoichiometric cis association of the tetraspanin CD151 with podocyte integrin ?3?1 is essential for stabilizing ?3?1 in an active ligand-binding conformation, thus maintaining the integrity of the glomerular filtration barrier (GFB). Other studies also show that activation of ?v?3 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 ?3?1 and ?v?3 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 ?v?3 remains to be clarified. In preliminary studies, we show that ?v?3 ectodomain binds CD151 with similar EC50 to ?3?1, that this interaction requires the active conformation of ?v?3 and is promoted by the ?v?3 inhibitors used in prior studies acting as partial agonists. These data lead us to propose and test the hypothesis that activation of ?v?3 in disease states sequesters CD151 away from binding to ?3?1, thus impairing optimal ?3?1 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 ?v and developed a novel class of ?v?3 inhibitors that are not partial agonists and that prevent rather than promote ?v?3/CD151 association, which will also allow us to examine the glomerular response to injury when ?v?3 is inactivated genetically or pharmacologically in rodent models of proteinuric kidney disease.