Transcriptional networks of progressive diabetic peripheral neuropathy in thedb/dbmouse model of type 2 diabetes: An inflammatory story

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Diabetic peripheral neuropathy is the most common complication of diabetes and a source of considerable morbidity. Numerous molecular pathways are linked to neuropathic progression, but it is unclear whether these pathways are altered throughout the course of disease. Moreover, the methods by which these molecular pathways are analyzed can produce significantly different results; as such it is often unclear whether previously published pathways are viable targets for novel therapeutic approaches. In the current study we examine changes in gene expression patterns in the sciatic nerve (SCN) and dorsal root ganglia (DRG) of db/db diabetic mice at 8, 16, and 24weeks of age using microarray analysis. Following the collection and verification of gene expression data, we utilized both self-organizing map (SOM) analysis and differentially expressed gene (DEG) analysis to detect pathways that were altered at all time points. Though there was some variability between SOM and DEG analyses, we consistently detected altered immune pathways in both the SCN and DRG over the course of disease. To support these results, we further used multiplex analysis to assess protein changes in the SCN of diabetic mice; we found that multiple immune molecules were upregulated at both early and later stages of disease. In particular, we found that matrix metalloproteinase-12 was highly upregulated in microarray and multiplex data sets suggesting it may play a role in disease progression.HIGHLIGHTSWe examined longitudinal transcriptomics patterns in SCN and DRG of db/db mice.Genes/pathways regulated across all stages of DPN are promising therapeutic targets.Immune-associated pathways were increased in both SCN and DRG at all time points.IFN-γ, IL-10, and MMP-12 proteins were upregulated in SCN during early and late DPN.These data indicate specific immune system involvement at all stages of DPN.

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