Cross-Species Identification of Conserved Glomerular Transcriptional Networks of Progressive Diabetic Nephropathy in Mouse and Man.
Jeffrey B Hodgin, Viji Nair, Hongyu Zhang, Ann Randolph, Raymond C Harris, Robert G Nelson, Frank C Brosius, Matthias Kretzler. University of Michigan, Ann Arbor; Vanderbilt University, Nashville, TN; NIDDK, Phoenix, AZ
Background: Mouse models of diabetic nephropathy (DN) are valuable tools, but no mouse model reliably exhibits all features of human disease, hindering our ability to identify specific factors that cause or predict DN. To define where mouse models of diabetic glomerulopathy (DG) faithfully recapitulate human DG on a functional level using a cross-species comparison to identify shared transcriptional networks.
Design: Transcriptional networks for diabetic humans and AMDCC mouse models were generated using glomerular mRNA, Affymetrix microarrays, transcriptional pathway mapping, and promoter modeling tools. The human transcriptional network was derived from albuminuric (>30 mg/g Alb/Cr) versus nonalbuminuric (<30 mg/g Alb/Cr) Pima Indians, a cohort with early, progressive DG, and from later stage diabetics versus living donor controls. Mouse transcriptional networks were derived from streptozotocin treated DBA/2 mice, db/db C57BLKS mice, and eNOS-deficient db/db C57BLKS mice, each versus control.
Results: Integrating the gene expression alterations with biological knowledge resulted in complex networks of 1000s of genes linked by multiple co-citations and promoter binding sites (Genomatix Bibliosphere). TALE (Tool for Approximate Large Graph Matching, University of Michigan) was used to align the human and mouse transcriptional networks to derive three conserved network structures for each human-mouse comparison, comprised of approximately 100 nodes representing key hubs of conserved regulatory events. Shared gene nodes were found in all three networks, many of them reflecting established pathogenetic mechanisms of diabetic complications including JAK-STAT, VEGF, c-kit, and HGF-R signaling pathways. Shared top biological processes included cytokine mediated signaling, response to steroid hormone, and JAK-STAT cascade.
Conclusions: Comparing TALE networks from early progressive DG (PIMA albuminuric versus nonalbuminuric) against established DG (albuminuric diabetics versus nondiabetics) revealed pathways specific to glomerular disease progression. This approach can guide the selection of disease pathways in mouse models that are the most relevant to the human disease process and identify new pathways that are excellent targets for future study.
Category: Kidney (does not include tumors)
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 241, Wednesday Afternoon