TY - JOUR
T1 - Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy
AU - Chang, Ying Shuang
AU - Kan, Hung Wei
AU - Hsieh, Yu Lin
N1 - Funding Information:
We sincerely thank Professor Tsonwin Hai of Ohio State University who kindly provided us with ATF3 knockout mice. This study was supported by grants from the Ministry of Science and Technology (107-2320-B037-022), Chi-Mei Medical Center, and Kaohsiung Medical University Research Foundation (107CM-KMU-09), Taiwan.
Publisher Copyright:
© 2019 Chang et al.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Activating transcription factor 3
KW - B-cell lymphoma-extra large
KW - Bcl-
KW - Diabetic peripheral neuropathy
KW - Neuropathic pain
KW - PKCε
KW - Protein kinase C epsilon
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U2 - 10.2147/JPR.S186699
DO - 10.2147/JPR.S186699
M3 - Article
AN - SCOPUS:85060676861
SN - 1178-7090
VL - 12
SP - 317
EP - 326
JO - Journal of Pain Research
JF - Journal of Pain Research
ER -
