The soluble
urokinase plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of
kidney diseases including primary and recurrent focal and
segmental glomerulosclerosis (FSGS),
diabetic nephropathy, and
acute kidney injuries (AKI). Elevated serum suPAR concentration is a negative prognostic
indicator in multiple critical clinical conditions. This study has examined the initial transduction steps used by suPAR in cultured mouse podocytes. We now report that the
receptor for advanced glycation end-products (RAGE) co-immunoprecipitates with αV and β3
integrin subunits, which have been previously shown to initiate suPAR signal transduction at the podocyte cell surface.
siRNA knock-down of RAGE attenuated Src phosphorylation evoked by either suPAR or by glycated
albumin (
AGE-BSA), a prototypical RAGE agonist. suPAR effects on Src phosphorylation were also blocked by the structurally dissimilar RAGE antagonists
FPS-ZM1 and
azeliragon, as well as by
cilengitide, an inhibitor of outside-in signaling through αV-
integrins.
FPS-ZM1 also blocked Src phosphorylation evoked by
AGE-BSA.
FPS-ZM1 blocked increases in cell surface
TRPC6 abundance, cytosolic
reactive oxygen species (ROS) and activation of the
small GTPase Rac1 evoked by either suPAR or
AGE-BSA. In addition,
FPS-ZM1 inhibited Src phosphorylation evoked by serum collected from a patient with recurrent FSGS during a relapse. The magnitude of this inhibition was indistinguishable from the effect produced by a
neutralizing antibody against suPAR. These data suggest that orally bioavailable small molecule RAGE antagonists could represent a useful therapeutic strategy for a wide range of clinical conditions associated with elevated serum suPAR, including primary FSGS and AKI.