Kidney Week

Abstract: TH-PO390

Engineered Immune Complexes with Galactose-Deficient IgA1: A New Model for IgA Nephropathy

Session Information

• Cell Signaling and Oxidative Stress
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Cell Biology

• 203 Growth Factors, Chemokines, Autacoids

Authors

• Reily, Colin, University of Alabama at Birmingham, Birmingham, Alabama, United States

Colin Reily,

• Huang, Zhi qiang, University of Alabama at Birmingham, Birmingham, Alabama, United States

Zhi qiang Huang,

• Xu, Nuo, university of alabama at birmingham, Birmingham, Alabama, United States

Nuo Xu,

• Moldoveanu, Zina, Univ of Alabama at Birmingham, Birmingham, Alabama, United States

Zina Moldoveanu,

• Novak, Lea, University of Alabama at Birmingham , Birmingham, Alabama, United States

Lea Novak,

• Hall, Stacy D., UAB, Birmingham, Alabama, United States

Stacy D. Hall,

• Brown, Rhubell T., University of Alabama at Birmingham , Birmingham, Alabama, United States

Rhubell T. Brown,

• Lewis, Terry L, University of Alabama at Birmingham , Birmingham, Alabama, United States

Terry L Lewis,

• Weaver, Casey T., University of Alabama at Birmingham , Birmingham, Alabama, United States

Casey T. Weaver,

• Julian, Bruce A., University of Alabama at Birmingham , Birmingham, Alabama, United States

Bruce A. Julian,

• Suzuki, Hitoshi, Juntendo University Faculty of Medicine, Tokyo, Japan

Hitoshi Suzuki,

• Willey, Christopher D., The University of Alabama at Birmingham, Birmingham, Alabama, United States

Christopher D. Willey,

• Novak, Jan, University of Alabama at Birmingham , Birmingham, Alabama, United States

Jan Novak,

Background

IgA nephropathy (IgAN) is an autoimmune disease characterized by circulating immune complexes (CIC) that deposit in the kidney and incite kidney injury. These CICs contain galactose-deficient IgA1 (Gd-IgA1) bound by Gd-IgA1-specific autoantibodies. Development of models of IgAN has been hindered because only humans and hominoid primates have IgA1 with its O-glycans. To address these issues, we developed an animal model by using in vitro-formed, engineered immune complexes (EIC) from human Gd-IgA1 and recombinant Gd-IgA1-specific IgG. In this study, we profiled kidney transcriptomes from mice injected with these EIC, controls, and human IgAN kidney biopsies.

Methods

EICs were formed from Gd-IgA1 and recombinant Gd-IgA1-specific antibody. EIC or Gd-IgA1 only were injected intravenously 3 times every other day in 8-week old immunodeficient mice. Kidneys were harvested 1d after last injection, and either snap frozen in liquid nitrogen for RNAseq analysis or fixed for pathologic analysis. RNAseq data sets were compared against published data from IgAN patient kidney biopsy samples, and pathway analysis was performed using the Broad Institute GSEA tool.

Results

Mice injected with EIC exhibited glomerular matrix expansion and hypercellularity, with no morphological changes observed in the control group. Using 0.5 log2 fold-change parameter, gene expression analysis found 118 genes up-regulated and 165 down-regulated in the EIC-injected vs. control mice. Pathway analysis between the EIC model and IgAN biopsies identified multiple pathways in common, including estrogen early and late response, matrisome, interferon gamma response, and epithelial to mesenchymal transition. In addition, similar genes between the EIC animal model and biopsies were found to be modified in a similar pattern and SDS/Western blotting of kidney tissue for selected targets showed protein expression followed mRNA changes for some genes.

Conclusion

Using EICs, we generated an IgAN passive mouse model that replicates some of the pathologic changes observed in renal biopsies of IgAN patients. This model thus provides a unique platform for testing disease-specific drugs for efficacy in reducing kidney damage from CICs.

Funding

• NIDDK Support