Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in
diabetic nerve and kidney disease.
Authors Hinder LM, Park M, Rumora AE, Hur J, Eichinger F, Pennathur S, Kretzler M,
Brosius FC, Feldman EL
Submitted By Junguk Hur on 4/3/2017
Status Published
Journal Journal of cellular and molecular medicine
Year 2017
Date Published
Volume : Pages Not Specified : Not Specified
PubMed Reference 28272773
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.

Investigators with authorship
Frank BrosiusUniversity of Arizona
Eva FeldmanUniversity of Michigan
Junguk HurUniversity of North Dakota
Matthias KretzlerUniversity of Michigan