Downregulation of glucose-6-phosphate dehydrogenase contributes to diabetic neuropathic pain through upregulation of toll-like receptor 4 in rats

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Abstract

Background and aim

Diabetic neuropathic pain is a refractory and disabling complication of diabetes mellitus. The pathogenesis of the diabetic neuropathic pain is still unclear, and treatment is insufficient. The aim of this study is to investigate the roles of glucose-6-phosphate dehydrogenase (G6PD) and toll-like receptor 4 (TLR4) in neuropathic pain in rats with diabetes.

Methods

Type 1 diabetes model was induced by intraperitoneal injection of streptozotocin (STZ, 75 mg/kg) in adult female Sprague-Dawley rats. Paw withdrawal threshold and paw withdrawal latency of rats were measured by von Frey filaments and thermal radiation, respectively. The expressions of G6PD and TLR4 in L4-L6 dorsal root ganglions (DRGs) were measured by western blotting and quantitative real-time polymerase chain reaction analysis. Fluorescent immunohistochemistry was employed to detect expressions of G6PD and TLR4 and co-location of G6PD with TLR4.

Results

The mRNA and protein expression levels of G6PD in DRGs were significantly decreased in diabetic rats when compared with age-matched control rats. Upregulation of G6PD by intrathecal injection of G6PD overexpression adenovirus markedly attenuated hindpaw pain hypersensitivity of diabetic rats. The mRNA and protein expression levels of TLR4 in DRGs of diabetic rats were significantly increased when compared with control rats. Intrathecal injection of TLR4-selective inhibitor CLI-095 attenuated diabetic pain in dose- and time-dependent manners. Furthermore, G6PD and TLR4 were co-localized in DRG neurons. Intrathecal injection of G6PD overexpression adenovirus greatly reduced TLR4 expression, while intrathecal injection of CLI-095 had no significant effect on G6PD expression in diabetic rats.

Conclusions

Our results suggest that decrease in G6PD expression was involved in diabetic peripheral neuropathic pain, which was most likely through upregulation of TLR4 expression in the DRGs of rats.

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Most cited references 40

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New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain.

Eva Feldman, David Bennett, Klaus-Armin Nave … (2017)

Pre-diabetes and diabetes are a global epidemic, and the associated neuropathic complications create a substantial burden on both the afflicted patients and society as a whole. Given the enormity of the problem and the lack of effective therapies, there is a pressing need to understand the mechanisms underlying diabetic neuropathy (DN). In this review, we present the structural components of the peripheral nervous system that underlie its susceptibility to metabolic insults and then discuss the pathways that contribute to peripheral nerve injury in DN. We also discuss systems biology insights gleaned from the recent advances in biotechnology and bioinformatics, emerging ideas centered on the axon-Schwann cell relationship and associated bioenergetic crosstalk, and the rapid expansion of our knowledge of the mechanisms contributing to neuropathic pain in diabetes. These recent advances in our understanding of DN pathogenesis are paving the way for critical mechanism-based therapy development.

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Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress.

Dan Ye, Zhi-Qiang Ling, Yue Xiong … (2014)

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway (PPP) and plays an essential role in the oxidative stress response by producing NADPH, the main intracellular reductant. G6PD deficiency is the most common human enzyme defect, affecting more than 400 million people worldwide. Here, we show that G6PD is negatively regulated by acetylation on lysine 403 (K403), an evolutionarily conserved residue. The K403 acetylated G6PD is incapable of forming active dimers and displays a complete loss of activity. Knockdown of G6PD sensitizes cells to oxidative stress, and re-expression of wild-type G6PD, but not the K403 acetylation mimetic mutant, rescues cells from oxidative injury. Moreover, we show that cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner. The SIRT2-mediated deacetylation and activation of G6PD stimulates PPP to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. We also identified KAT9/ELP3 as a potential acetyltransferase of G6PD. Our study uncovers a previously unknown mechanism by which acetylation negatively regulates G6PD activity to maintain cellular NADPH homeostasis during oxidative stress. © 2014 The Authors.

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High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and beta-cell apoptosis.

R. Stanton, Joseph Loscalzo, Yingyi Zhang … (2010)

Patients with type 2 diabetes lose beta cells, but the underlying mechanisms are incompletely understood. Glucose-6-phosphate dehydrogenase (G6PD) is the principal source of the major intracellular reductant, NADPH, which is required by many enzymes, including enzymes of the antioxidant pathway. Previous work from our laboratory has shown that high glucose impairs G6PD activity in endothelial and kidney cells, which leads to decreased cell survival. Pancreatic beta cells are highly sensitive to increased ROS. This study aimed to determine whether G6PD and NADPH play central roles in beta-cell survival. Human and mouse islets, MIN6 cell line, and G6PD deficient mice were studied. High glucose inhibited G6PD expression and activity. Inhibition of G6PD with siRNA led to increased ROS and apoptosis, decreased proliferation, and impaired insulin secretion. High glucose decreased insulin secretion, which was improved by overexpressing G6PD. G6PD-deficient mice had smaller islets and impaired glucose tolerance compared with control mice, which suggests that G6PD deficiency per se leads to beta-cell dysfunction and death. G6PD plays an important role in beta-cell function and survival. High-glucose-mediated decrease in G6PD activity may provide a mechanistic explanation for the gradual loss of beta cells in patients with diabetes.

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Author and article information

Journal

Journal ID (nlm-ta): Mol Pain

Journal ID (iso-abbrev): Mol Pain

Journal ID (publisher-id): MPX

Journal ID (hwp): spmpx

Title: Molecular Pain

Publisher: SAGE Publications (Sage CA: Los Angeles, CA )

ISSN (Electronic): 1744-8069

Publication date (Electronic): 26 April 2019

Publication date Collection: 2019

Volume: 15

Electronic Location Identifier: 1744806919838659

Affiliations

[1 ]Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, P. R. China

[2 ]Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, P. R. China

Author notes

[*]

These authors contributed to this work equally

[*]Guang-Yin Xu, Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou 215123, P. R. China. Email: guangyinxu@ 123456suda.edu.cn

Article

Publisher ID: 10.1177_1744806919838659

DOI: 10.1177/1744806919838659

PMC ID: 6487759

PubMed ID: 30838902

SO-VID: 17cac00d-8396-4678-8993-5b98d7ee2ae1

License:

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 5 January 2019

Date revision received : 13 February 2019

Date accepted : 18 February 2019

Funding

Funded by: Natural Science Foundation of Jiangsu Province, FundRef http://doi.org/10.13039/501100004608;

Award ID: BK20181172

Funded by: National Natural Science Foundation of China, FundRef http://dx.doi.org/10.13039/501100001809;

Award ID: 31730040

Award ID: 81471041

Award ID: 81471137

Funded by: Jiangsu Youth Medical Talents Project, FundRef ;

Award ID: QNRC2016874

Custom metadata

cover-date January-December 2019

ScienceOpen disciplines: Molecular medicine

Keywords: diabetes,neuropathic pain,dorsal root ganglion,glucose-6-phosphate dehydrogenase,toll-like receptor 4

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ScienceOpen disciplines: Molecular medicine

Keywords: diabetes, neuropathic pain, dorsal root ganglion, glucose-6-phosphate dehydrogenase, toll-like receptor 4

Downregulation of glucose-6-phosphate dehydrogenase contributes to diabetic neuropathic pain through upregulation of toll-like receptor 4 in rats

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Abstract

Background and aim

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Most cited references 40

New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain.

Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress.

High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and beta-cell apoptosis.

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