Abstract
Autophagy is a catabolic process which is involved in the development of many diseases including diabetes mellitus and its complications. Hyposalivation is a common complication of diabetes mellitus, whereas its mechanism remains unclear. Here, we observed that the stimulated salivary flow rate of SMG was significantly decreased in db/db mice, a diabetic mice model. The expressions of aquaporin 5 (AQP5), a water channel protein, were decreased, whereas the mRNA level of AQP5 was increased in SMGs of both diabetic patients and mice. Under transmission electron microcope, more autophagosomes were detected in diabetic SMGs. Expressions of autophagy related proteins LC3II, Beclin-1 and ATG5 were increased, meanwhile autophagy substrate p62 was decreased in SMGs of diabetic patients and mice, indicating that autophagy was activated in diabetic SMG. Double immunofluorescence staining showed that the colocalization of AQP5 and LC3 was increased in SMGs of diabetic mice. In cultured SMG-C6 cells, high glucose (HG), but not high osmotic pressure, reduced AQP5 protein expression and induced autophagy. Moreover, inhibition of autophagy by 3-methyladenin, an autophagy inhibitor, or by autophagy-related gene 5 siRNA, decreased HG-induced AQP5 reduction in SMG-C6 cells. Additionally, the expression of p-p85, p-Akt and p-mTOR were decreased in HG-treated SMG-C6 cells. Pretreatment with 740Y-P, a PI3K agonist, significantly suppressed HG-induced autophagy and AQP5 degradation. Taken together, these results indicate that autophagy plays a crucial role in AQP5 degradation in diabetic SMG via PI3K/Akt/mTOR signaling pathway, which contributes to the dysfunction of diabetic SMG. Our study provides a novel mechanism of diabetic hyposalivation.
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Acknowledgements
We thank Dr. David O. Quissell (University of Colorado Health Science Center, USA) for the generous gift of rat SMG-C6 cell line. We would like to thank Jiazeng Su, Wenxuan Zhu, Kefu Zhang, Yanyan Zhang for their work in the collection of patients’ information. This work was supported by National Natural Science Foundation of China (81570993, 81671005) and Beijing Natural Science Foundation of China (7162100).
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Huang, Y., Shi, X., Mao, Q. et al. Aquaporin 5 is degraded by autophagy in diabetic submandibular gland. Sci. China Life Sci. 61, 1049–1059 (2018). https://doi.org/10.1007/s11427-018-9318-8
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DOI: https://doi.org/10.1007/s11427-018-9318-8