Abstract: FR-PO1056
ABIN1 Contributes to Glomerulonephritis via Induction of IP-10 Expression and Activity
Session Information
- Glomerular Diseases: Immunology and Inflammation - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Powell, David W., University of Louisville, Louisville, Kentucky, United States
- Vieyra, Mark B., University of Louisville, Louisville, Kentucky, United States
- Tandon, Shweta, University of Louisville, Louisville, Kentucky, United States
- Korte, Erik, University of Louiville, Louisville, Kentucky, United States
- Barati, Michelle T., University of Louisville, Louisville, Kentucky, United States
- Gagnon, Kenneth, University of Louisville, Louisville, Kentucky, United States
- McLeish, Kenneth R., University of Louisville, Louisville, Kentucky, United States
- Caster, Dawn J., University of Louisville, Louisville, Kentucky, United States
Group or Team Name
- Immune-Mediated Kidney Disease Laboratory
Background
Our research to define genetic risks of glomerular inflammation identified variants in TNIP1 as risks for development of lupus nephritis. TINIP1 encodes ABIN1, a physiological inhibitor of NF-κB and MAPK-mediated inflammation. We reported that loss of ABIN1 function in podocytes (ABIN1[D485N]) exacerbates immune-mediated podocyte injury and enhances podocyte cytokine and chemokine production in vivo and in vitro, leading to enhanced neutrophil recruitment and activation. The NF-κB-mediated chemokine IFN-γ-inducible protein 10 (IP-10) had a > 20-fold increase in gene expression in podocytes with loss of ABIN1 activity. The current study tested the hypothesis that IP-10 contributes to ABIN1-mediated podocyte injury and glomerular inflammation.
Methods
In vitro exocytosis (flow cytometry for granule markers CD66b and CD35) and chemotaxis (transwell migration assay) of primary human neutrophils was measured following incubation with recombinant IP-10 w/wo a known activator FMLF. Urinary IP-10 levels were measured by ELISA 24 h following administration of nephrotoxic anti-GBM antibody in WT and ABIN1[D485N] mice. Proteinuria was measured 24 h following administration of anti-GBM in WT and ABIN1[D485N] mice w/wo pre-treatment with neutralizing IP-10 antibody.
Results
Recombinant IP-10 did not activate neutrophil chemotaxis alone, but significantly primed the response to FMLF. IP-10 activated neutrophil exocytosis alone and also primed the FMLF response. Urinary IP-10 levels were significantly higher in ABIN1[D485N] mice than WT mice 24 h-post anti-GBM administration. Anti-GBM-induced proteinuria was inhibited by pre-treatment with IP-10 antibody in WT and ABIN1[D485N] mice.
Conclusion
Our data suggest that genetic disruption of ABIN1 in podocytes results in enhance production of IP-10 during experimental glomerulonephritis and that IP-10 production regulates neutrophil activation and contributes to glomerular damage leading to proteinuria. Our data provide clinical relevance for the finding that IP-10 is a urinary biomarker for lupus nephritis (LN). The use of IP-10 neutralizing antibody for treatment of ulcerative colitis and rheumatoid arthritis, suggests a new therapeutic approach for patients with LN associated with variants for TNIP1 or other NF-κB or MAPK regulatory genes.
Funding
- Other NIH Support