Abstract: SA-PO622
Glomerular Gene Coexpression Networks Suggest Pathogenic Mechanisms in a Mouse Model of HIV-Associated Nephropathy
Session Information
- Glomerular Diseases: Immunology, Inflammation - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Gonzalez-Vicente, Agustin, Cleveland Clinic, Cleveland, Ohio, United States
- Wu, Zhenzhen, Cleveland Clinic, Cleveland, Ohio, United States
- Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
- Barisoni, Laura, Duke University, Durham, North Carolina, United States
- Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
- Bruggeman, Leslie A., Cleveland Clinic, Cleveland, Ohio, United States
- Sedor, John R., Cleveland Clinic, Cleveland, Ohio, United States
- O'Toole, John F., Cleveland Clinic, Cleveland, Ohio, United States
Background
HIV-associated nephropathy (HIVAN) is an important cause of renal failure in African-Americans. The Tg26-transgenic mouse replicates key features of HIVAN including podocyte dedifferentiation. We hypothesize that glomerular gene coexpression networks from Tg26 mice will provide insights into HIVAN pathogenesis.
Methods
Glomerular-transcriptomes were obtained from 6-week old wild-type and Tg26-HIVAN4 mice of both sexes. Preliminary analysis demonstrated a strong sex effect on gene expression. In order to control the covariate sex, two networks were generated using weighted gene-correlation network analysis (WGCNA): 1) all mice sex-adjusted, 2) Consensus network between unadjusted gene expression form female and male mice. Coexpression modules significantly correlated with HIV-transgenes in both analysis were compared, identifying overlapping gene lists. These lists were evaluated for canonical pathway enrichment with IPA.
Results
1113 overlapping genes were found between 2 consensus and 5 sex-adjusted modules significantly correlated with HIV transgenes. Intersecting genes were pooled into 4 functional groups based on pathways enrichment. The first group represented the initial response to HIV transgenes with pathways leading to the activation of macrophages and secretion of chemoattractant molecules. The second group represented the migration of immune cells to the “infection” site and the activation of the inflammasome. The third group was enriched with integrin signaling pathways. As integrin interactions are widely used by migrating immune cells, this group likely supports the immune response on groups 1 and 2. Finally, the fourth functional group was largely enriched with cell cycle pathways, reflecting that in collapsing forms of focal segmental glomerulosclerosis such as HIVAN, differentiated glomerular cells are recruited back into the cell cycle.
Conclusion
Gene-coexpression network analysis detected modules matching the chain of events in the progression of HIVAN in the Tg26-HIVAN4 mice. We also identified sex as a strong driver of gene expression. However, this sex effect did not impact disease pathways in Tg26-HIVAN4 mice, but could be relevant in understanding sexual dimorphism in other kidney diseases.
Funding
- NIDDK Support