Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in
diabetic nerve and kidney disease
#MMPMID28272773
Hinder LM
; Park M
; Rumora AE
; Hur J
; Eichinger F
; Pennathur S
; Kretzler M
; Brosius FC 3rd
; Feldman EL
J Cell Mol Med
2017[Sep]; 21
(9
): 2140-2152
PMID28272773
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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.
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