Bmal1 Deficiency Provokes Dry Mouth By Down-Regulating Itpr2/3

Exploring the influence of circadian rhythm and its key molecule BMAL1 on salivary gland secretion. Mice with rhythm disorder were constructed by knockout of Bmal1, the changes of salivary gland function were detected, and saliva flow, tear film stability and tear secretion were observed. The molecular mechanism of BMAL1 regulation of salivary gland secretion function was revealed by histomorphology and biomolecular detection techniques. Compared with normal mice, the parotid gland secretion dysfunction of BMAL1 knockout mice was manifested as significantly reduced saliva flow, decreased expression of secretory fluid markers, lactoferrin and lysozyme, acinar cell vacuolation and atrophy phenotype of secretory gland, and significantly increased apoptosis of secretory gland cells. Further, by analyzing the ChIP-Seq data and Western-Blot and immunohistochemical verification, it was found that compared with normal mice, the expression of ITPR2/3, salivation-related proteins, in Bmal1 knockout mice was significantly reduced. Chromatin immunoprecipitation techniques have shown that BMAL1 directly regulates ITPR2/3 transcription. By local injection of Itpr2/3 recombinant adenovirus, BMAL1-knockout mice improved secretory gland dysfunction, manifested by significant recovery of saliva flow. This research confirmed that Bmal1 deletion can significantly induce the vacuolation and atrophic changes of acinar cells, trigger the apoptosis process, and lead to overall glandular dysfunction, abnormal secretion function, and eventually dry mouth and other pathological manifestations. The key role of BMAL1-mediated ITPR2/3 activation in regulating saliva and lacrimal gland secretion was revealed, and restoring ITPR2/3 could alleviate dry mouth symptoms.