Abstract
Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes. In this study, we employed a systems biology approach to identify DPN-related transcriptional pathways conserved across human and various murine models. Eight microarray datasets on peripheral nerve samples from murine models of type 1 (streptozotocin-treated) and type 2 (db/db and ob/ob) diabetes of various ages and human subjects with non-progressive and progressive DPN were collected. Differentially expressed genes (DEGs) were identified between non-diabetic and diabetic samples in murine models, and non-progressive and progressive human samples using a unified analysis pipeline. A transcriptional network for each DEG set was constructed based on literature-derived gene-gene interaction information. Seven pairwise human-vs-murine comparisons using a network-comparison program resulted in shared sub-networks including 46 to 396 genes, which were further merged into a single network of 688 genes. Pathway and centrality analyses revealed highly connected genes and pathways including LXR/RXR activation, adipogenesis, glucocorticoid receptor signalling, and multiple cytokine and chemokine pathways. Our systems biology approach identified highly conserved pathways across human and murine models that are likely to play a role in DPN pathogenesis and provide new possible mechanism-based targets for DPN therapy.
Highlights
Over the past decade, with the advent of high-throughput gene expression profiling assays such as microarrays and RNA-Seq, we and others have examined genome-wide gene expression changes from the peripheral nerve tissues of various diabetic murine models[5,6,7,8,9] and human subjects[10,11] with diabetes
The data from the type 1 diabetes mellitus (T1DM) model were originally generated from male DBA/2J mice treated with streptozotocin (STZ) at 10 weeks that were terminated at 34 weeks[9]
We compared transcriptomic changes in peripheral nerves isolated from humans and mouse models of T1DM and type 2 diabetes mellitus (T2DM) at various stages of Diabetic peripheral neuropathy (DPN) to identify potential molecular pathways contributing to disease
Summary
With the advent of high-throughput gene expression profiling assays such as microarrays and RNA-Seq, we and others have examined genome-wide gene expression changes from the peripheral nerve tissues of various diabetic murine models[5,6,7,8,9] and human subjects[10,11] with diabetes. One limitation of the previous studies, including ours, is that the analyses didn’t account for the differences in species, strains, procedure of diabetes induction, and diabetes duration Another critical issue that hasn’t been addressed far is the identification of common injurious pathways and networks conserved across various mouse models of diabetes as well as between mouse and human. The human sural nerve data used was generated using the Affymetrix Human Genome U133 Plus 2.0 array platform[7] As previously reported these samples were evaluated for features of DPN and were separated into progressive and non-progressive groups based on the myelinated fibre density lost over a 52 week period[7]
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