DNMT3a‐triggered downregulation of K<sub>2p</sub>1.1 gene in primary sensory neurons contributes to paclitaxel‐induced neuropathic pain

Mao, Qingxiang; Wu, Shaogen; Gu, Xiechong; Du, Shouying; Mo, Kai; Sun, Linlin; Cao, Jing; Bekker, Alex; Chen, Liyong; Tao, Yuan Xiang

doi:10.1002/ijc.32155

Cited by 39 publications

(62 citation statements)

References 42 publications

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“…RNA extraction and real-time reverse transcription PCR assays were carried out as described previously ( 48 ). Briefly, total RNA was extracted by the TRIzol method (Invitrogen, Thermo Fisher Scientific Inc.), treated with DNase (New England Biolabs), and reverse-transcribed using ThermoScript reverse transcriptase (Invitrogen, Thermo Fisher Scientific Inc.) and oligo (dT) primers (Invitrogen, Thermo Fisher Scientific Inc.).…”

Section: Methodsmentioning

confidence: 99%

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Huang¹,

Fu²,

Gao³

et al. 2020

JCI Insight

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Thalamic pain, a type of central poststroke pain, frequently occurs following ischemia/hemorrhage in the thalamus. Current treatment of this disorder is often ineffective, at least in part due to largely unknown mechanisms that underlie thalamic pain genesis. Here, we report that hemorrhage caused by microinjection of type IV collagenase or autologous whole blood into unilateral ventral posterior lateral nucleus and ventral posterior medial nucleus of the thalamus increased the expression of Fgr, a member of the Src family nonreceptor tyrosine kinases, at both mRNA and protein levels in thalamic microglia. Pharmacological inhibition or genetic knockdown of thalamic Fgr attenuated the hemorrhage-induced thalamic injury on the ipsilateral side and the development and maintenance of mechanical, heat, and cold pain hypersensitivities on the contralateral side. Mechanistically, the increased Fgr participated in hemorrhage-induced microglial activation and subsequent production of TNF-α likely through activation of both NF-κB and ERK1/2 pathways in thalamic microglia. Our findings suggest that Fgr is a key player in thalamic pain and a potential target for the therapeutic management of this disorder.

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Section: Methodsmentioning

confidence: 99%

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Huang¹,

Fu²,

Gao³

et al. 2020

JCI Insight

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“…The TurboFect in vivo transfection reagent (Thermo Scientific, Wilmington, NC, USA) was used as an in vivo delivery vehicle for pcDNA3-MEG3 to prevent degradation and enhance transfection efficiency as described previously (Mao et al, 2019; Xu et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

Long noncoding RNA MEG3 suppresses podocyte injury in diabetic nephropathy by inactivating Wnt/β-catenin signaling

Che

Deng

Xie

et al. 2019

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BackgroundDiabetic nephropathy (DN) is one of the principal complications of diabetes and podocyte injury plays an important role in the DN pathogenesis. Wnt/β-catenin signaling overactivation confers podocyte injury and promotes multiple types of renal disease. However, the underlying mechanism of Wnt/β-catenin signaling activation in DN progression has not been fully elucidated. Long noncoding RNA (lncRNA) is a large class of endogenous RNA molecules lacking functional code capacity and which participates in the pathogenesis of human disease, including DN.MethodA diabetes model was constructed by intraperitoneal injection of Streptozotocin in rats. The MPC5 cells were used to create the in vitro model. Western blot and Quantitative reverse-transcriptase-PCR were used to examine the expression of protein and mRNA. The migrated capacity was analyzed by Transwell migration assay. The cell viability was detected by CCK8.ResultsIn the present study, we revealed the association of lncRNA Maternally Expressed Gene 3 (MEG3) with aberrant activation of Wnt/β-catenin signaling and the role of MEG3/Wnt axis in podocyte injury. We found that high glucose (HG) treatment suppressed MEG3 expression in cultured podocytes, activated Wnt/β-catenin signaling and caused podocyte injury as indicated by the downregulation of podocyte-specific markers (podocin and synaptopodin) and the upregulation of snail1 and α-smooth muscle actin. Overexpression of MEG3 attenuated HG-induced podocyte injury by reducing Wnt/β-catenin activity, repressing cell migration, reactive oxygen species production and increasing the viability of podocytes. Furthermore, we provided evidences that restoration of Wnt/β-catenin signaling by specific agonist impeded the protective effect of MEG3 on podocyte injury. Current results demonstrated that MEG3/Wnt axis plays an important role in fostering podocyte injury and may serve as a potential therapeutic target for the treatment of DN.ConclusionlncRNA MEG3 ameliorates podocyte injury in DN via inactivating Wnt/β-catenin signaling.

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“…Control experiments for rabbit anti-DNMT1 included substitution of normal rabbit serum for the primary antiserum, omission of the primary antiserum, and preabsorption of the primary antibody with overdose of the antigen. The specificity of remaining primary antisera has been identified previously Shao et al, 2017;Sun et al, 2017;Xu et al, 2017;Zhao et al, 2017;Mo et al, 2018;Mao et al, 2019;Yuan et al, 2019). The sections finally mounted using VectaMount permanent mounting medium (Vector Laboratories) or Vectashield plus DAPI mounting medium (Vector Laboratories).…”

Section: Methodsmentioning

confidence: 99%

“…The specificity of rabbit anti-DNMT1 was examined in the following control experiments, including substitution of normal rabbit serum for the primary antiserum, omission of the primary antiserum, and preabsorption of the primary antibody with overdose of the antigen. The specificity of remaining primary antisera was reported previously (Lee et al, 2011;Zhao et al, 2013Zhao et al, , 2017Fan et al, 2014;Li et al, 2015Sun et al, 2017;Mo et al, 2018;Du et al, 2019;Mao et al, 2019) or from vendors' data sheets. Membranes were further incubated with anti-mouse or anti-rabbit HRP-conjugated secondary antibody (1: 3000, Jackson ImmunoResearch Laboratories) for 2 h at room temperature and visualized by Western peroxide reagent and luminol/enhancer reagent (Clarity Western ECL Substrate, Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

“…Conventionally, DNMT3a and DNMT3b function as de novo DNMTs to revers-ibly methylate unmethylated DNA, whereas DNMT1 is classified as the primary DNMT to maintain DNA methylation that has been established at the genome (Jeltsch, 2006;Siedlecki and Zielenkiewicz, 2006). The contribution of de novo DNMT3atriggered DNA methylation to neuropathic pain genesis was reported Shao et al, 2017;Sun et al, 2017;Zhao et al, 2017;Mo et al, 2018;Mao et al, 2019;Yuan et al, 2019). Expression of DNMT3a, but not DNMT3b, is increased in the injured DRG following peripheral nerve injury .…”

Section: Introductionmentioning

confidence: 99%

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Contribution of DNMT1 to Neuropathic Pain Genesis Partially through Epigenetically Repressing Kcna2 in Primary Afferent Neurons

Sun¹,

Gu²,

Pan³

et al. 2019

J. Neurosci.

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Expressional changes of pain-associated genes in primary sensory neurons of DRG are critical for neuropathic pain genesis. DNA methyltransferase (DNMT)-triggered DNA methylation silences gene expression. We show here that DNMT1, a canonical maintenance methyltransferase, acts as the de novo DNMT and is required for neuropathic pain genesis likely through repressing at least DRG Kcna2 gene expression in male mice. Peripheral nerve injury upregulated DNMT1 expression in the injured DRG through the transcription factor cAMP response element binding protein-triggered transcriptional activation of Dnmt1 gene. Blocking this upregulation prevented nerve injury-induced DNA methylation within the promoter and 5Ј-untranslated region of Kcna2 gene, rescued Kcna2 expression and total Kv current, attenuated hyperexcitability in the injured DRG neurons, and alleviated nerve injury-induced pain hypersensitivities. Given that Kcna2 is a key player in neuropathic pain, our findings suggest that DRG DNMT1 may be a potential target for neuropathic pain management.In the present study, we reported that DNMT1, a canonical DNA maintenance methyltransferase, is upregulated via the activation of the transcription factor CREB in the injured DRG after peripheral nerve injury. This upregulation was responsible for nerve injury-induced de novo DNA methylation within the promoter and 5Ј-untranslated region of the Kcna2 gene, reductions in Kcna2 expression and Kv current and increases in neuronal excitability in the injured DRG. Since pharmacological inhibition or genetic knockdown of DRG DNMT1 alleviated nerve injury-induced pain hypersensitivities, DRG DNMT1 contributes to neuropathic pain genesis partially through repression of DRG Kcna2 gene expression.

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DNMT3a‐triggered downregulation of K_2p1.1 gene in primary sensory neurons contributes to paclitaxel‐induced neuropathic pain

Cited by 39 publications

References 42 publications

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Long noncoding RNA MEG3 suppresses podocyte injury in diabetic nephropathy by inactivating Wnt/β-catenin signaling

Contribution of DNMT1 to Neuropathic Pain Genesis Partially through Epigenetically Repressing Kcna2 in Primary Afferent Neurons

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DNMT3a‐triggered downregulation of K2p1.1 gene in primary sensory neurons contributes to paclitaxel‐induced neuropathic pain

Cited by 39 publications

References 42 publications

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Long noncoding RNA MEG3 suppresses podocyte injury in diabetic nephropathy by inactivating Wnt/β-catenin signaling

Contribution of DNMT1 to Neuropathic Pain Genesis Partially through Epigenetically Repressing Kcna2 in Primary Afferent Neurons

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DNMT3a‐triggered downregulation of K_2p1.1 gene in primary sensory neurons contributes to paclitaxel‐induced neuropathic pain