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

Lucy M. Hinder, Meeyoung Park, Amy E. Rumora, Junguk Hur, Felix Eichinger, Subramaniam Pennathur, Matthias Kretzler, Frank C. Brosius, Eva L. Feldman

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2140-2152
Number of pages13
JournalJournal of cellular and molecular medicine
Volume21
Issue number9
DOIs
StatePublished - Sep 1 2017

Fingerprint

pioglitazone
Diabetic Nephropathies
Gene Expression Profiling
Metabolic Networks and Pathways
RNA
Diabetic Neuropathies
Peripheral Nervous System Diseases
NAD
Kidney
Kidney Glomerulus
Gene Expression
Myelinated Nerve Fibers
Sciatic Nerve
Nerve Fibers
Type 2 Diabetes Mellitus
Insulin Resistance
Cell Death
Inflammation

Keywords

  • diabetic nephropathy
  • diabetic peripheral neuropathy
  • pioglitazone
  • type 2 diabetes

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

Cite this

Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease. / Hinder, Lucy M.; Park, Meeyoung; Rumora, Amy E.; Hur, Junguk; Eichinger, Felix; Pennathur, Subramaniam; Kretzler, Matthias; Brosius, Frank C.; Feldman, Eva L.

In: Journal of cellular and molecular medicine, Vol. 21, No. 9, 01.09.2017, p. 2140-2152.

Research output: Contribution to journalArticle

Hinder, LM, Park, M, Rumora, AE, Hur, J, Eichinger, F, Pennathur, S, Kretzler, M, Brosius, FC & Feldman, EL 2017, 'Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease', Journal of cellular and molecular medicine, vol. 21, no. 9, pp. 2140-2152. https://doi.org/10.1111/jcmm.13136
Hinder, Lucy M. ; Park, Meeyoung ; Rumora, Amy E. ; Hur, Junguk ; Eichinger, Felix ; Pennathur, Subramaniam ; Kretzler, Matthias ; Brosius, Frank C. ; Feldman, Eva L. / Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease. In: Journal of cellular and molecular medicine. 2017 ; Vol. 21, No. 9. pp. 2140-2152.
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