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      Is Open Access

      Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy

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          Abstract

          Background

          Skin denervation that develops in patients with diabetes mellitus as a neuropathic manifestation is known as diabetic peripheral neuropathy (DPN). Skin denervation is parallel to neuronal injuries that alter intracellular signaling. To date, the correlation between nerve injury and the activation of intracellular responses to neuropathic manifestations has not been elucidated; specifically, whether activating transcription factor 3 (ATF3) is responsible for neuronal injury and a critical molecule that modulates the activation of intracellular protein kinase C epsilon (p-PKCε) and pain development in DPN is a crucial question.

          Methods

          To address, ATF3 knockout ( atf3 −/− group, C57/B6 genetic background) and wild-type mice ( atf3 +/+ group) received a single dose of streptozotocin (200 mg/kg) to generate a mouse model of DPN.

          Results

          Both atf3 +/+ and atf3 −/− mice exhibited hyperglycemia and the same pathology of skin denervation at posttreatment month 2, but only atf3 +/+ mice developed thermal hyperalgesia ( P<0.001) and mechanical allodynia ( P=0.002). The atf3 +/+ group, but not the atf3 −/− group, had preferential ATF3 upregulation on p-PKCε(+) neurons with a ratio of 37.7%±6.1% in p-PKCε(+):ATF3(+) neurons ( P<0.001). In addition, B-cell lymphoma-extra large (Bcl- XL), an antiapoptotic Bcl2 family protein, exhibited parallel patterns to p-PKCε (ie, Bcl- XL upregulation was reversed in atf3 −/− mice). These two molecules were colocalized and increased by approximately two-fold in the atf3 +/+ group compared with the atf3 −/− group (30.0%±3.4% vs 13.7% ± 6.2%, P=0.003). Furthermore, linear analysis results showed that the densities of p-PKCε and Bcl- XL had a reverse linear relationship with the degrees of thermal hyperalgesia and mechanical allodynia.

          Conclusion

          Collectively, this report suggested that ATF3 is a critical upstream molecule that modulates p-PKCε and Bcl- XL expression, which consequently mediated the development of neuropathic manifestation in DPN.

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          Most cited references 36

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          Ethical guidelines for investigations of experimental pain in conscious animals.

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            Diabetic neuropathy: cellular mechanisms as therapeutic targets.

            In patients with diabetes, nerve injury is a common complication that leads to chronic pain, numbness and substantial loss of quality of life. Good glycemic control can decrease the incidence of diabetic neuropathy, but more than half of all patients with diabetes still develop this complication. There is no approved treatment to prevent or halt diabetic neuropathy, and only symptomatic pain therapies, with variable efficacy, are available. New insights into the mechanisms leading to the development of diabetic neuropathy continue to point to systemic and cellular imbalances in metabolites of glucose and lipids. In the PNS, sensory neurons, Schwann cells and the microvascular endothelium are vulnerable to oxidative and inflammatory stress in the presence of these altered metabolic substrates. This Review discusses the emerging cellular mechanisms that are activated in the diabetic milieu of hyperglycemia, dyslipidemia and impaired insulin signaling. We highlight the pathways to cellular injury, thereby identifying promising therapeutic targets, including mitochondrial function and inflammation.
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              Role for activating transcription factor 3 in stress-induced beta-cell apoptosis.

              Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced beta-cell apoptosis. First, ATF3 is induced in beta cells by signals relevant to beta-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-kappaB and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in beta cells develop abnormal islets and defects secondary to beta-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine- or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced beta-cell apoptosis.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2019
                14 January 2019
                : 12
                : 317-326
                Affiliations
                [1 ]Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, ylhsieh@ 123456kmu.edu.tw
                [2 ]Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
                [3 ]Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan, ylhsieh@ 123456kmu.edu.tw
                Author notes
                Correspondence: Yu-Lin Hsieh, Department of Anatomy, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan, Tel +886 7 312 1101ext2144, Fax +886 7 311 9849, Email ylhsieh@ 123456kmu.edu.tw
                Article
                jpr-12-317
                10.2147/JPR.S186699
                6338122
                © 2019 Chang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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