Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease

J Cell Mol Med. 2017 Sep;21(9):2140-2152. doi: 10.1111/jcmm.13136. Epub 2017 Mar 8.

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.

Keywords: diabetic nephropathy; diabetic peripheral neuropathy; pioglitazone; type 2 diabetes.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Computational Biology
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / metabolism*
  • Diabetic Neuropathies / genetics*
  • Diabetic Neuropathies / metabolism*
  • Gene Expression Profiling*
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / pathology
  • Male
  • Metabolic Networks and Pathways* / genetics
  • Mice, Inbred C57BL
  • Nerve Fibers / drug effects
  • Nerve Fibers / pathology
  • Organ Specificity / genetics
  • Pioglitazone
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Sequence Analysis, RNA*
  • Thiazolidinediones / pharmacology

Substances

  • RNA, Messenger
  • Thiazolidinediones
  • Pioglitazone