Nonimmune cell-derived ICOS ligand functions as a renoprotective [alpha]v[beta]3 integrin-selective antagonist

Soluble urokinase receptor (suPAR) is a circulatory molecule that activates [alpha]v[beta]3 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'...

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Bibliographic Details
Published in:The Journal of clinical investigation 2019-04, Vol.129 (4), p.1713
Main Authors: Koh, Kwi Hye, Cao, Yanxia, Mangos, Steve, Tardi, Nicholas J, Dande, Ranadheer R, Lee, Ha Won, Samelko, Beata, Altintas, Mehmet M, Schmitz, Vincent P, Lee, Hyun, Mukherjee, Kamalika, Peev, Vasil, Cimbaluk, David J, Reiser, Jochen, Hahm, Eunsil
Format: Article
Language:English
Subjects:
Antibodies
Arginine
Aspartate
B cells
Cell proliferation
Development and progression
Glycine
Integrins
Kidney diseases
Novels
Peptides
Proteinuria
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Summary:Soluble urokinase receptor (suPAR) is a circulatory molecule that activates [alpha]v[beta]3 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 [alpha]v[beta]3 integrin. Contrary to ICOSL's immune-regulatory role, ICOSL in nonhematopoietic cells limited the activation of [alpha]v[beta]3 integrin. Specifically, ICOSL contains the arginine-glycine-aspartate (RGD) motif, which allowed for a high-affinity and selective binding to [alpha]v[beta]3 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 [alpha]v[beta]3 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 [alpha]v[beta]3-selective antagonist to maintain glomerular filtration.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI123386