Transcriptional networks of murine diabetic peripheral neuropathy and nephropathy: common and distinct gene expression patterns

Hur, Junguk; O’Brien, Phillipe D.; Nair, Viji; Hinder, Lucy M.; McGregor, Brett A.; Jagadish, H. V.; Kretzler, Matthias; Brosius, Frank C.; Feldman, Eva L.

doi:10.1007/s00125-016-3913-8

Cited by 37 publications

(40 citation statements)

References 38 publications

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“…In 2017, it was estimated that 451 million people worldwide suffer from diabetes, including 30 million Americans [1,2], with type 2 diabetes (T2D) accounting for approximately 90% to 95% of the diagnosed cases. T2D is primarily characterized by hyperglycaemia, hyperlipidaemia, and insulin resistance [3]. Both subjects with type 1 (T1D) and T2D experience diabetes-related microvascular complications which have a negative impact on the quality of life and affect multiple tissues including the nerve (diabetic neuropathy), kidney (diabetic nephropathy) and eye (diabetic retinopathy) [4].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus

et al. 2019

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DNA methylation is an epigenetic mechanism important for the regulation of gene expression, which plays a vital role in the interaction between genetic and environmental factors. Aberrant epigenetic changes are implicated in the pathogenesis of diabetes and diabetic complications, but the role of DNA methylation in diabetic peripheral neuropathy (DPN) is not well understood. Therefore, our aim in this study was to explore the role of DNA methylation in the progression of DPN in type 2 diabetes. We compared genome-wide DNA methylation profiles of human sural nerve biopsies from subjects with stable or improving nerve fibre counts to biopsies from subjects with progressive loss of nerve fibres. Nerve fibre counts were determined by comparing myelinated nerve fibre densities between an initial and repeat biopsy separated by 52 weeks. Subjects with significant nerve regeneration (regenerators) and subjects with significant nerve degeneration (degenerators) represent the two extreme DPN phenotypes. Using reduced representation bisulfite sequencing, we identified 3,460 differentially methylated CpG dinucleotides between the two groups. The genes associated with differentially methylated CpGs were highly enriched in biological processes that have previously been implicated in DPN such as nervous system development, neuron development, and axon guidance, as well as glycerophospholipid metabolism and mitogen-activated protein kinase (MAPK) signalling. These findings are the first to provide a comprehensive analysis of DNA methylation profiling in human sural nerves of subjects with DPN and suggest that epigenetic regulation has an important role in the progression of this prevalent diabetic complication.

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Section: Introductionmentioning

confidence: 99%

Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus

et al. 2019

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“…Although the metabolic response of these tissues to diabetes has historically been thought to be similar and downstream of altered glucose metabolism (20), we recently found that glucose and fatty acid oxidation are tissue specific and dissimilar among the three diabetic end-organ target tissues of kidney, nerve, and retina (21). Transcriptomic analysis identified several pathways involved in lipid biosynthesis that were enriched in both the diabetic mouse kidney and nerve (21), although dysregulation of gene expression in the diabetic kidney and nerve was overall discordant (22,23). Transcriptomic data indicates altered lipid synthesis, but there is a lack of information on broader lipid changes derived from synthesis in these diabetic tissues and how any lipid changes relate to mRNA expression.…”

mentioning

confidence: 99%

Shared and distinct lipid-lipid interactions in plasma and affected tissues in a diabetic mouse model

Sas

Lin

Rajendiran

et al. 2018

Journal of Lipid Research

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Lipids are ubiquitous metabolites with diverse functions; abnormalities in lipid metabolism appear to be related to complications from multiple diseases, including type 2 diabetes. Through technological advances, the entire lipidome has been characterized and researchers now need computational approaches to better understand lipid network perturbations in different diseases. Using a mouse model of type 2 diabetes with microvascular complications, we examined lipid levels in plasma and in renal, neural, and retinal tissues to identify shared and distinct lipid abnormalities. We used correlation analysis to construct interaction networks in each tissue, to associate changes in lipids with changes in enzymes of lipid metabolism, and to identify overlap of coregulated lipid subclasses between plasma and each tissue to define subclasses of plasma lipids to use as surrogates of tissue lipid metabolism. Lipid metabolism alterations were mostly tissue specific in the kidney, nerve, and retina; no lipid changes correlated between the plasma and all three tissue types. However, alterations in diacylglycerol and in lipids containing arachidonic acid, an inflammatory mediator, were shared among the tissue types, and the highly saturated cholesterol esters were similarly coregulated between plasma and each tissue type in the diabetic mouse. Our results identified several patterns of altered lipid metabolism that may help to identify pathogenic alterations in different tissues and could be used as biomarkers in future research into diabetic microvascular tissue damage.

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“…As seen in Fig. 4B, at all the time points (24,48, and 72 h), HDAC1 and HDAC5 were increased with high-glucose stimulation (P , 0.05). Particularly at 72 h after high-glucose stimulation, HDAC1 and HDAC5 were respectively increased by 3.48 and 3.00 times, respectively, compared with normal-glucose treatment (P , 0.05).…”

Section: High Glucose Increased Hdac1 and Hdac5 Expression In Schwannmentioning

confidence: 60%

STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy

Wang

et al. 2019

FASEB j.

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Schwann cells are the main supportive cells of the peripheral nerves. Schwann cells suffer inhibition of autophagy under hyperglycemia treatment in diabetic peripheral neuropathy (DPN). However, the exact mechanism is still not fully elucidated. We first observed the decrease of autophagy markers (LC3‐II/LC3‐I, P62) in the sciatic nerves of diabetic mice vs. normal mice, accompanied with the loss of myelinated nerve fibers and abnormal myelin sheath. In line with this, LC3‐II/LC3‐I and P62 were also significantly reduced in high glucose—treated rat Schwann cell 96 (RSC96) cells compared with normal glucose—treated cells. Furthermore, we found that trichostatin A [an inhibitor of histone deacetylase (HDAC)] evidently improved LC3‐II/LC3‐I in high glucose—treated RSC96 cells, without an effect on P62 expression. Again, HDAC1 and HDAC5 were revealed to be increased in RSC96 cells stimulated with high glucose. Inhibition of HDAC1 but not HDAC5 by small hairpin RNA vector enhanced LC3‐II/LC3‐I in high glucose—cultured RSC96 cells. In addition, LC3‐II conversion regulators [autophagy‐related protein (Atg)3, Atg5, and Atg7] were detected in high glucose—treated and HDAC1‐knockdown RSC96 cells, and Atg3 was proven to be the key target of HDAC1. The presuppression of Atg3 offset the improvement of LC3‐II/LC3‐I resulting from HDAC1 inhibition in high glucose—treated RSC96 cells. The Janus kinase (JAK)—signal transducer and activator of transcription (STAT) signaling pathway was activated in RSC96 cells treated with high glucose, which was indicated by increased STAT3 phosphorylation. Blocking STAT3 phosphorylation by chemical inhibitor AG490 induced HDAC1 down‐regulation followed by increases in Atg3 and LC3‐II/LC3‐I. Interestingly, we also found that AG490 treatment enhanced P62 expression in high glucose—stimulated RSC96 cells. Taken together, our findings demonstrate that hyperglycemia inhibits LC3‐II/LC3‐I in an HDAC1‐Atg3—dependent manner and decreases P62 expression in an HDAC‐independent manner via the JAK‐STAT3 signaling pathway in the Schwann cells of DPN.—Du, W., Wang, N., Li, F. Jia, K., An, J., Liu, Y., Wang, Y., Zhu, L., Zhao, S. Hao, J. STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy. FASEB J. 33, 8008–8021 (2019). http://www.fasebj.org

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Transcriptional networks of murine diabetic peripheral neuropathy and nephropathy: common and distinct gene expression patterns

Cited by 37 publications

References 38 publications

Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus

Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus

Shared and distinct lipid-lipid interactions in plasma and affected tissues in a diabetic mouse model

STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy

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