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Abstract: FR-PO726

Therapeutic Potential of Inducible Co-stimulator Ligand for Treating avb3-Mediated Glomerular Damage

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology

Authors

  • Xu, Yan, Rush University Medical Center, Chicago, Illinois, United States
  • Spear, Ryan, Rush University Medical Center, Chicago, Illinois, United States
  • Cao, Yanxia, Rush University Medical Center, Chicago, Illinois, United States
  • Koh, Kwi Hye, Rush University Medical Center, Chicago, Illinois, United States
  • Mangos, Steve, Rush University Medical Center, Chicago, Illinois, United States
  • Endlich, Nicole, University Medicine Greifswald, Greifswald, Germany
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States
  • Hahm, Eunsil, Rush University Medical Center, Chicago, Illinois, United States
Background

Activation of avb3 integrin is an early pathological process in several podocytopathies leading to glomerular disease with no treatment options available. We recently identified inducible co-stimulator ligand (ICOSL) as a renoprotective agent that acts as an antagonist of avb3 integrin. We tested the precise mechanistic action of ICOSL in protecting the kidney from injury and evaluated in vivo efficacy of ICOSL and its small peptide in proteinuric animal models.

Methods

Expression dynamics of ICOSL during glomerular injury was established by performing quantitative PCR on 3 main glomerular cell types (human podocytes, glomerular endothelial cells, and mesangial cells) after different injury stimuli. We generated double knockout (DKO) mice (ICOS-/ICOSL-) to explore the importance of ICOSL’s canonical receptor to renoprotection. ACR and BUN measurements were used to evaluate renal function in DKO and control mice that were subjected to STZ-induced diabetic nephropathy. ICOSL’s binding specificity and affinity toward RGD-binding Integrins was tested using surface plasmon resonance (SPR). A 19 amino acid portion of ICOSL was tested for its ability to target podocyte avb3 integrin using an in vitro podocyte adhesion assay, and for its ability to mitigate LPS-induced proteinuria in ICOSL KO mice.

Results

Glomerular ICOSL expression is regulated by immunological insults, not by conditions that cause oxidative stress. Among the cell types tested, podocytes are the predominant producers of ICOSL and could be stimulated to express ICOSL under immunological stress. Conversely, mechanical stress resulted in reduced ICOSL expression. KO mouse models treated with STZ demonstrate that the renoprotective function of ICOSL is independent of ICOS. Among the 7 different RGD-binding integrins tested, only αvβ3 integrin shows strong and preferential binding to ICOSL. Both full-length and a 19-mer portion of ICOSL protein could bind podocytes through avb3 integrin and reverse LPS-induced proteinuria in ICOSL KO mice.

Conclusion

Our data suggest that the glomerular expression of ICOSL mainly occurs in podocytes and can be triggered by immunological insults. Given the highly selective binding characteristics to avb3 integrin, ICOSL and ICOSL-based small peptides may offer novel and safe therapeutic options for treating avb3-mediated glomerular diseases.

Funding

  • NIDDK Support