Soluble urokinase receptor (suPAR) is a circulatory molecule that activates αvβ3 integrin on podocytes， causes foot process effacement， and contributes to proteinuric kidney disease. While active integrin can be targeted by antibodies and small molecules， endogenous inhibitors haven't been discovered yet. Here we report what we believe is a novel renoprotective role for the inducible costimulator ligand (ICOSL) in early kidney disease through its selective binding to podocyte αvβ3 integrin. Contrary to ICOSL's immune-regulatory role， ICOSL in nonhematopoietic cells limited the activation of αvβ3 integrin. Specifically， ICOSL contains the arginine-glycine-aspartate (RGD) motif， which allowed for a high-affinity and selective binding to αvβ3 and modulation of podocyte adhesion. This binding was largely inhibited either by a synthetic RGD peptide or by a disrupted RGD sequence in ICOSL. ICOSL binding favored the active αvβ3 rather than the inactive form and showed little affinity for other integrins. Consistent with the rapid induction of podocyte ICOSL by inflammatory stimuli， glomerular ICOSL expression was increased in biopsies of early-stage human proteinuric kidney diseases. Icosl deficiency in mice resulted in an increased susceptibility to proteinuria that was rescued by recombinant ICOSL. Our work identified a potentially novel role for ICOSL， which serves as an endogenous αvβ3-selective antagonist to maintain glomerular filtration.