Structure and Function of Integrins in the Kidney

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.

Grant Number: 5R01DK088327-12
NIH Institute/Center: NIH
Principal Investigator: M. AMIN ARNAOUT