The impairment of the intestinal epithelial barrier and subsequent bacterial translocation are common in aging individuals, contributory to several local and systematic disorders. However, the underlying mechanism of the age-related degeneration has not been fully understood. In this study, we demonstrated that the intestinal KIT signaling declined and de-activated with aging, parallel with epithelial barrier dysfunction. Endoplasmic reticulum stress (ERS)/unfolded protein response (UPR) was obviously increased during aging. The ERS and its downstream IRE1α were highly activated in the aging colonic epithelium. Furthermore, by the use of Tunicamycin (Tm)-induced ERS mouse and cell models, we uncovered that the activity of the ERS/IRE1α accelerated the protein degradation of KIT via ubiquitin-proteasome pathway. The deficiency of KIT signaling further reduced the transcription of the tight junction protein Claudin-3. Of significance, Artesunate (ART) could be capable of ameliorating the detrimental effect of ERS/IRE1α, indicated by the re-gained KIT and Claudin-3 expressions and the restoration of the intestinal epithelial barrier. In conclusion, our present study provided novel evidence elucidating the ERS/IRE1α-induced loss of KIT and Claudin-3 in the aging colonic epithelium and also shed light on the protective effect of Artesunate on the intestinal epithelial barrier by blocking ERS/IRE1α activity during aging.
Keywords: Aging; Artesunate; Claudin-3; Endoplasmic reticulum stress; Intestinal epithelial barrier; KIT.
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