ZBTB20 mediates stress‐induced visceral hypersensitivity via activating the NF‐κB/transient receptor potential channel pathway

Abstract

BackgroundPsychological stress is a major trigger for visceral hypersensitivity (VH) in irritable bowel syndrome. The zinc finger protein ZBTB20 (ZBTB20) is implicated in somatic nociception via modulating transient receptor potential (TRP) channels, but its role in the development of VH is unclear. This study aimed to investigate the role of ZBTB20/TRP channel axis in stress‐induced VH.MethodsRats were subjected to water avoidance stress (WAS) for 10 consecutive days. Small interfering RNA (siRNA) targeting ZBTB20 was intrathecally administered. Inhibitors of TRP channels, stress hormone receptors, and nuclear factor kappa‐B (NF‐κB) were administered. Visceromotor response to colorectal distension was recorded. Dorsal root ganglia (DRGs) were dissected for Western blot, coimmunoprecipitation, and chromatin immunoprecipitation. The DRG‐derived neuron cell line was applied for specific research.Key ResultsWAS‐induced VH was suppressed by the inhibitor of TRPV1, TRPA1, or TRPM8, with enhanced expression of these channels in L6‐S2 DRGs. The inhibitor of glucocorticoid receptor or β2‐adrenergic receptor counteracted WAS‐induced VH and TRP channel expression. Concurrently, WAS‐induced stress hormone‐dependent ZBTB20 expression and NF‐κB activation in DRGs. Intrathecally injected ZBTB20 siRNA or an NF‐κB inhibitor repressed WAS‐caused effect. In cultured DRG‐derived neurons, stress hormones promoted nuclear translocation of ZBTB20, which preceded p65 nuclear translocation. And, ZBTB20 siRNA suppressed stress hormone‐caused NF‐κB activation. Finally, WAS enhanced p65 binding to the promoter of TRPV1, TRPA1, or TRPM8 in rat DRGs.Conclusions and InferencesZBTB20 mediates stress‐induced VH via activating NF‐κB/TRP channel pathway in nociceptive sensory neurons.

Sequencing Reveals miRNAs Enriched in the Developing Mouse Enteric Nervous System

“…Neither have been studied in the context of the bowel previously. Zbtb20 , however, has been shown to mediate stress-induced visceral hypersensitivity in rats through its expression in dorsal root ganglia [ 56 ]. Mice lacking Zbtb20 display multiple metabolic defects, many of which are independent of liver function [ 57 ].…”