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Nonimmune cell–derived ICOS ligand functions as a renoprotective αvβ3 integrin–selective antagonist
Kwi Hye Koh, … , Jochen Reiser, Eunsil Hahm
Kwi Hye Koh, … , Jochen Reiser, Eunsil Hahm
Published February 12, 2019
Citation Information: J Clin Invest. 2019;129(4):1713-1726. https://doi.org/10.1172/JCI123386.
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Research Article Nephrology Article has an altmetric score of 14

Nonimmune cell–derived ICOS ligand functions as a renoprotective αvβ3 integrin–selective antagonist

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Abstract

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.

Authors

Kwi Hye Koh, Yanxia Cao, Steve Mangos, Nicholas J. Tardi, Ranadheer R. Dande, Ha Won Lee, Beata Samelko, Mehmet M. Altintas, Vincent P. Schmitz, Hyun Lee, Kamalika Mukherjee, Vasil Peev, David J. Cimbaluk, Jochen Reiser, Eunsil Hahm

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Figure 2

ICOSL binds to active αvβ3 integrin through its RGD motif.

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ICOSL binds to active αvβ3 integrin through its RGD motif.
(A) Schematic...
(A) Schematic of a gold surface with ICOSL protein on a sensor chip CM5 and associated protein (αvβ3 integrin) over which buffer is flown in SPR assay. (B–I) SPR sensorgrams depicting interaction of immobilized human ICOSL (hICOSL, B–D) or mouse ICOSL (mICOSL, E–I) with αvβ3 integrin. These bindings were tested in the presence (B and E, active form of αvβ3) or absence (C and F, inactive form of one with EDTA in the binding buffer) of Mn2+. (D and G) SPR used in an inhibition experiment with cRGDfv. Injection of αvβ3 integrin only (D, 120 nM αvβ3 or G, 150 nM αvβ3) resulted in a binding signal for immobilized hICOSL or mICOSL alone (pink line). Preincubation with cRGDfv (3 μM or 15 μM) significantly reduced the binding for ICOSL, indicating that the RGD peptide competes with ICOSL for binding to αvβ3 (orange line). cRGDfv alone was used as a control (green line). (H and I) SPR sensorgrams showing the binding between WT (H) or mutant (I) mICOSL protein and αvβ3 integrin in the presence of physiologically relevant divalent ions, Ca2+ (0.2 mM) and Mg2+ (0.1 mM). The average KD values were determined from at least 3 independent experiments. Rate constants (ka and kd) were determined by kinetic fitting (black dotted line) of the sensorgrams using 1-to-1 Langmuir binding equation, and KD values for B, E, and H were calculated by kd/ka (B, KD = 16.2 ± 4.0 nM for hICOSL/αvβ3 with Mn2+; E, KD = 24.2 ± 6.5 nM for mICOSL/αvβ3 with Mn2+; H, KD = 21.3 ± 1.2 nM for WT mICOSL/αvβ3 with Ca2+/Mg2+). KD values for C, F, and I were calculated from steady-state affinity fittings (C, KD = 411.8 ± 164.1 nM for hICOSL/αvβ3; F, KD ≥ 2 mM for mICOSL/αvβ3; I, KD = 0.83 ± 0.8 mM for mutant mICOSL/αvβ3 with Ca2+/Mg2+).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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