The role of TNF-alpha/NF-kappa B pathway on the up-regulation of voltage-gated sodium channel Nav1.7 in DRG neurons of rats with diabetic neuropathy

Huang, Yangliang; Zang, Ying; Zhou, Lijun; Gui, Wen-Shan; Liu, Xianguo; Zhong, Yi

doi:10.1016/j.neuint.2014.05.012

Cited by 68 publications

(59 citation statements)

References 45 publications

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“…For example, a previous study reported that pretreatment with PDTC could attenuate the pain behaviors of rats with diabetic neuropathy [21]. A study evaluating the relationship between TLR4 and mucosal injury demonstrated that moderate TLR4 signaling was the best for mucosal healing: insufficient TLR4 signaling caused bacterial translocation and poor mucosal healing, while too much TLR4 signaling induced severe inflammation or even cancer [22].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Involvement of the TLR4/NF-κB Signaling Pathway in the Repair of Esophageal Mucosa Injury in Rats with Gastroesophageal Reflux Disease

Yu¹,

Wang²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Numerous studies have highlighted the activation of NF-κB in the esophageal mucosa during the early stages of gastroesophageal reflux disease (GERD). The present study aimed to investigate the role of the TLR4/NF-κB signaling pathway in GERD rat models. Methods: Wistar rats (n = 60) were recruited to establish a GERD animal model. Distal esophageal pH was assessed, followed by determination of the contents of thiobarbituric acid-reactive species (TBARS) and reactive oxygen species (ROS) in esophageal mucosa homogenate. ELISA was employed to detect the levels of inflammatory factors (IL-6, IL-8, IL-10 and TNF-α) in esophageal mucosa. The expression of MMP-3, MPP-9, Cldn1 and Cldn4 was determined by immunohistochemistry. RT-qPCR and western blot analysis were applied to evaluate the protein expressions in TLR4/NF-κB signaling pathway, while TUNEL staining was utilized to examine the apoptosis rate in the esophageal mucosal tissues. Results: Distal esophageal pH of the rats was higher in the GERD + PDTC group than in other groups. Levels of inflammatory factors in esophageal mucosal tissues were downregulated with the inhibition of NF-κB, which was determined to be associated with the decreased contents of TBARS and ROS. Moreover, decreased MMP-3 and MPP-9 in addition to elevated Cldn1 and Cldn4 were detected in the esophageal mucosa as a result of the inactivation of NF-κB. The TLR4/NF-κB signaling pathway-related proteins (TLR4, NF-κB and IκBα); the rate of apoptosis was demonstrated to be suppressed in the GERD + PDTC group, while inactivating NF-κB was found to alleviate the tissue damage observed in the esophageal mucosa. Conclusion: The key findings of the current study demonstrate that the inactivation of the TLR4/NF-κB signaling pathway alleviates oxidative stress injury and promotes the repair of esophageal mucosal injury among rats with GERD, highlighting a potential novel GERD mechanism.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Involvement of the TLR4/NF-κB Signaling Pathway in the Repair of Esophageal Mucosa Injury in Rats with Gastroesophageal Reflux Disease

Yu¹,

Wang²,

Zhang³

et al. 2018

Cell Physiol Biochem

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“…We particularly focused on NF‐κB transcription factors, as they were reported to induce SCN9A expression in neurons (Huang et al., 2014) and are well‐known regulators of senescence (Acosta et al., 2008; Bernard et al., 2004; Chien et al., 2011; Ferrand et al., 2015). We examined whether or not the inhibition of NF‐κB transcription factors, either by constitutively expressing a stabilized version of IKBA (mIKBA), a well‐known inhibitor of NF‐κB, or by knocking down the expression of RELA (Figures 2a and S3a), the main subunit of the NF‐κB transcription factors, blocked the induction of SCN9A during OIS.…”

Section: Resultsmentioning

confidence: 99%

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

et al. 2018

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SummaryOncogenic signals lead to premature senescence in normal human cells causing a proliferation arrest and the elimination of these defective cells by immune cells. Oncogene‐induced senescence (OIS) prevents aberrant cell division and tumor initiation. In order to identify new regulators of OIS, we performed a loss‐of‐function genetic screen and identified that the loss of SCN9A allowed cells to escape from OIS. The expression of this sodium channel increased in senescent cells during OIS. This upregulation was mediated by NF‐κB transcription factors, which are well‐known regulators of senescence. Importantly, the induction of SCN9A by an oncogenic signal or by p53 activation led to plasma membrane depolarization, which in turn, was able to induce premature senescence. Computational and experimental analyses revealed that SCN9A and plasma membrane depolarization mediated the repression of mitotic genes through a calcium/Rb/E2F pathway to promote senescence. Taken together, our work delineates a new pathway, which involves the NF‐κB transcription factor, SCN9A expression, plasma membrane depolarization, increased calcium, the Rb/E2F pathway and mitotic gene repression in the regulation of senescence. This work thus provides new insight into the involvement of ion channels and plasma membrane potential in the control of senescence.

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“…14 It is therefore reasonable to hypothesize that TNF-α may be a significant contributor to sensitization of VGSCs under PDN conditions. Nuclear factor-kappa B signal pathway may also be involved in this process since we have demonstrated that nuclear factor-kappa B was upregulated in rat DRGs innervating the hindpaw 36,37 and the stomach.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] Furthermore, dysregulation of VGSCs in injured sensory neurons is also involved in the development of painful peripheral neuropathy in a rat model of diabetes. [14][15][16][17] However, roles for Na V 1.7 and Na V 1.8 in colonic hypersensitivity in streptozotocin (STZ)-induced diabetic rats remain unknown. Therefore, we hypothesized that colonic hypersensitivity correlated with sensitization of VGSCs in DRG neurons innervating the colon in rat with diabetes.…”

Section: Introductionmentioning

confidence: 99%

Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes

Song

Zhang

et al. 2015

J Neurogastroenterol Motil

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Background/AimsPatients with long-standing diabetes often demonstrate intestinal dysfunction and abdominal pain. However, the pathophysiology of abdominal pain in diabetic patients remains elusive. The purpose of study was to determine roles of voltage-gated sodium channels in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. MethodsDiabetic models were induced by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in adult female rats, while the control rats received citrate buffer only. Behavioral responses to colorectal distention were used to determine colonic sensitivity in rats. Colon projection DRG neurons labeled with DiI were acutely dissociated for measuring excitability and sodium channel currents by whole-cell patch clamp recordings. Western blot analysis was employed to measure the expression of Na V 1.7 and Na V 1.8 of colon DRGs. ResultsSTZ injection produced a significantly lower distention threshold than control rats in responding to colorectal distention. STZ injection also depolarized the resting membrane potentials, hyperpolarized action potential threshold, decreased rheobase and increased frequency of action potentials evoked by 2 and 3 times rheobase and ramp current stimulation. Furthermore, STZ injection enhanced neuronal sodium current densities of DRG neurons innervating the colon. STZ injection also led to a significant upregulation of Na V 1.7 and Na V 1.8 expression in colon DRGs compared with age and sex-matched control rats. ConclusionsOur results suggest that enhanced neuronal excitability following STZ injection, which may be mediated by upregulation of Na V 1.7 and Na V 1.8 expression in DRGs, may play an important role in colonic hypersensitivity in rats with diabetes.

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The role of TNF-alpha/NF-kappa B pathway on the up-regulation of voltage-gated sodium channel Nav1.7 in DRG neurons of rats with diabetic neuropathy

Cited by 68 publications

References 45 publications

Involvement of the TLR4/NF-κB Signaling Pathway in the Repair of Esophageal Mucosa Injury in Rats with Gastroesophageal Reflux Disease

Involvement of the TLR4/NF-κB Signaling Pathway in the Repair of Esophageal Mucosa Injury in Rats with Gastroesophageal Reflux Disease

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes

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