Dataset Information

Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli.

ABSTRACT: 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.

SUBMITTER: Hodgin JB

PROVIDER: S-EPMC3526018 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli.

Hodgin Jeffrey B JB Nair Viji V Zhang Hongyu H Randolph Ann A Harris Raymond C RC Nelson Robert G RG Weil E Jennifer EJ Cavalcoli James D JD Patel Jignesh M JM Brosius Frank C FC Kretzler Matthias M

Diabetes 20121108 1

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 eN ...[more]

PMID: 23139354

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Project description:Aims/hypothesisDiabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN) are two common microvascular complications of type 1 and type 2 diabetes mellitus that are associated with a high degree of morbidity. In this study, using a variety of systems biology approaches, our aim was to identify common and distinct mechanisms underlying the pathogenesis of these two complications.MethodsOur previously published transcriptomic datasets of peripheral nerve and kidney tissue, derived from murine models of type 1 diabetes (streptozotocin-injected mice) and type 2 diabetes (BKS-db/db mice) and their respective controls, were collected and processed using a unified analysis pipeline so that comparisons could be made. In addition to looking at genes and pathways dysregulated in individual datasets, pairwise comparisons across diabetes type and tissue type were performed at both gene and transcriptional network levels to complete our proposed objective.ResultsGene-level analysis identified exceptionally high levels of concordant gene expression in DN (94% of 2,433 genes), but not in DPN (54% of 1,558 genes), between type 1 diabetes and type 2 diabetes. These results suggest that common pathogenic mechanisms exist in DN across diabetes type, while in DPN the mechanisms are more distinct. When these dysregulated genes were examined at the transcriptional network level, we found that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway was significantly dysregulated in both complications, irrespective of diabetes type.Conclusions/interpretationUsing a systems biology approach, our findings suggest that common pathogenic mechanisms exist in DN across diabetes type, while in DPN the mechanisms are more distinct. We also found that JAK-STAT signalling is commonly dysregulated among all datasets. Using such approaches, further investigation is warranted to determine whether the same changes are observed in patients with diabetic complications.

Dataset Information

Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli.

Publications

Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli.

Similar Datasets

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