title: Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease.
abstract: Treating insulin resistance with pioglitazone normalizes renal function and improves small nerve fibre function and architecture; however, it does not affect large myelinated nerve fibre function in mouse models of type 2 diabetes (T2DM), indicating that pioglitazone affects the body in a tissue-specific manner. To identify distinct molecular pathways regulating diabetic peripheral neuropathy (DPN) and nephropathy (DN), as well those affected by pioglitazone, we assessed DPN and DN gene transcript expression in control and diabetic mice with or without pioglitazone treatment. Differential expression analysis and self-organizing maps were then used in parallel to analyse transcriptome data. Differential expression analysis showed that gene expression promoting cell death and the inflammatory response was reversed in the kidney glomeruli but unchanged or exacerbated in sciatic nerve by pioglitazone. Self-organizing map analysis revealed that mitochondrial dysfunction was normalized in kidney and nerve by treatment; however, conserved pathways were opposite in their directionality of regulation. Collectively, our data suggest inflammation may drive large fibre dysfunction, while mitochondrial dysfunction may drive small fibre dysfunction in T2DM. Moreover, targeting both of these pathways is likely to improve DN. This study supports growing evidence that systemic metabolic changes in T2DM are associated with distinct tissue-specific metabolic reprogramming in kidney and nerve and that these changes play a critical role in DN and small fibre DPN pathogenesis. These data also highlight the potential dangers of a 'one size fits all' approach to T2DM therapeutics, as the same drug may simultaneously alleviate one complication while exacerbating another.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Hinder
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Meeyoung
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Rumora
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA.
authors.forename: Junguk
authors.initials: J
authors.lastname: Hur
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Eichinger
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.|Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Brosius
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000818:Animals; D019295:Computational Biology; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: diabetic nephropathy; diabetic peripheral neuropathy; pioglitazone; type 2 diabetes