Identification of Cross-Species Shared Transcriptional Networks of Diabetic Nephropathy in Human and Mouse Glomeruli
- Jeffrey B. Hodgin1,
- Viji Nair2,
- Hongyu Zhang2,
- Ann Randolph2,
- Raymond C. Harris3,
- Robert G. Nelson4,
- E. Jennifer Weil4,
- James D. Cavalcoli5,
- Jignesh M. Patel6,
- Frank C. Brosius III2,7⇓ and
- Matthias Kretzler5,2
- 1Department of Pathology, University of Michigan, Ann Arbor, Michigan
- 2Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- 3Department of Medicine, Vanderbilt University, Nashville, Tennessee
- 4Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
- 5Department of Bioinformatics and Computational Medicine, University of Michigan, Ann Arbor, Michigan
- 6Department of Computer Sciences, University of Wisconsin, Madison, Wisconsin
- 7Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
- Corresponding author: Frank C. Brosius III, .
J.B.H. and V.N. contributed equally to this study.
Murine models are valuable instruments in defining the pathogenesis of diabetic nephropathy (DN), but they only partially recapitulate disease manifestations of human DN, limiting their utility. To define the molecular similarities and differences between human and murine DN, we performed a cross-species comparison of glomerular transcriptional networks. Glomerular gene expression was profiled in patients with early type 2 DN and in three mouse models (streptozotocin DBA/2, C57BLKS db/db, and eNOS-deficient C57BLKS db/db mice). Species-specific transcriptional networks were generated and compared with a novel network-matching algorithm. Three shared human–mouse cross-species glomerular transcriptional networks containing 143 (Human-DBA STZ), 97 (Human-BKS db/db), and 162 (Human-BKS eNOS−/− db/db) gene nodes were generated. Shared nodes across all networks reflected established pathogenic mechanisms of diabetes complications, such as elements of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and vascular endothelial growth factor receptor (VEGFR) signaling pathways. In addition, novel pathways not previously associated with DN and cross-species gene nodes and pathways unique to each of the human–mouse networks were discovered. The human–mouse shared glomerular transcriptional networks will assist DN researchers in selecting mouse models most relevant to the human disease process of interest. Moreover, they will allow identification of new pathways shared between mice and humans.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1667/-/DC1.
See accompanying commentary, p. 31.
- Received December 1, 2011.
- Accepted July 14, 2012.
- © 2013 by the American Diabetes Association.
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