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Kidney Week

Abstract: TH-PO801

ICOSL in Non-Immune Cells Functions as an Inducible Potent αvβ3 Integrin-Selective Antagonist to Prevent Early Kidney Disease

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Koh, Kwi Hye, Rush University Medical Center, Chicago, Illinois, United States
  • Cao, Yanxia, Rush University Medical Center, Chicago, Illinois, United States
  • Mangos, Steve, Rush University Medical Center, Chicago, Illinois, United States
  • Tardi, Nicholas J., Rush University Medical Center, Chicago, Illinois, United States
  • Dande, Ranadheer, Rush University Medical Center, Chicago, Illinois, United States
  • Lee, Ha Won, Rush University Medical Center, Chicago, Illinois, United States
  • Samelko, Beata, Rush University Medical Center, Chicago, Illinois, United States
  • Altintas, Mehmet M., Rush University Medical Center, Chicago, Illinois, United States
  • Schmitz, Vincent Paul, Rush University Medical Center, Chicago, Illinois, United States
  • Lee, Hyun, Univ. of Illinois at Chicago, Chicago, Illinois, United States
  • Peev, Vasil, Rush University Medical Center, Chicago, Illinois, United States
  • Cimbaluk, David J., Rush University Medical Center, Chicago, Illinois, United States
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States
  • Hahm, Eunsil, Rush University Medical Center, Chicago, Illinois, United States
Background

ICOSL, the ligand for the inducible co-stimulator (ICOS), was the third member of the B7 superfamily discovered, is mainly expressed by antigen presenting cells (APCs), and functions in regulating T cell mediated immune responses. ICOSL has traditionally been assigned the fundamental role as an exclusive ligand for ICOS and was thought to be restricted to the immune system. As such, its potential function in non-hematopoietic cells under disease conditions remains completely unexplored.

Methods

In vitro and in vivo approaches were used to conduct the following analyses: qPCR, immunohistochemistry, surface plasmon resonance, cellular adhesion assays, ACR and BUN level measurements, electron microscopy, and bone marrow transplantations. Available on-line databases were used for 3D-modeled homology structure analysis. Rescue experiments involved injection of recombinant ICOSL into ICOSL KO mice.

Results

We find that unlike other B7 co-stimulatory molecules, ICOSL contains a known integrin-binding motif: arginine-glycine-aspartic (RGD), and selectively binds to αvβ3 but not to α3β1 integrin. Indeed, this binding depends on the activation state of αvβ3 integrin and is largely inhibited by the presence of synthetic RGD peptide, a selective antagonist of αvβ3. We also find that the RGD motif present in ICOSL is functionally active and modulates the αvβ3 integrin-dependent adhesion of podocytes. Consistent with the rapid induction of podocyte ICOSL expression by inflammatory stimuli, glomerular ICOSL expression is greatly increased at early stages of human proteinuric kidney diseases such as focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN). Furthermore, ICOSL deficiency results in an increased susceptibility to kidney injury and severe proteinuria in mice, and can be rescued by recombinant ICOSL injection.

Conclusion

Here we report a novel, renoprotective role for ICOSL in early kidney disease through its selective binding to active αvβ3 integrin. Our work identifies a novel role for ICOSL: protecting the kidney filter from injury by serving as a potent αvβ3-selective antagonist, and provides new insights into various pathological diseases associated with aberrant αvβ3 activation.

Funding

  • NIDDK Support