Endoplasmic reticulum stress contributes to NMDA-induced pancreatic β-cell dysfunction in a CHOP-dependent manner
2019
Huang, Xiao-Ting | Liu, Wei | Zhou, Yong | Sun, Mei | Sun, Chen-Chen | Zhang, Chen-Yu | Tang, Si-Yuan
Accumulating evidence suggest that endoplasmic reticulum (ER) stress is an important mechanism underlying the development of diabetes. We have reported that sustained treatment with N-methyl-d-aspartate (NMDA) results in apoptotic β-cell death and impairs insulin secretion. However, the molecular mechanism responsible for NMDA-induced β-cell dysfunction remains largely obscure. Thus, this study aimed to determine whether sustained activation of NMDA receptors (NMDARs) causes β-cell dysfunction through ER stress.Primary mouse islets and MIN6 mouse pancreatic β-cells were treated with NMDA for 24 h or high-glucose for 72 h. After the treatment, glucose-stimulated insulin secretion (GSIS) and the expression of ER stress markers were measured, respectively. In vivo, the expression of ER stress markers was measured in the pancreas of diabetic mice treated with or without NMDARs inhibitor Memantine.NMDA treatment caused an increase in the expression of ER stress markers (ATF4, CHOP, GRP78, and Xbp1s) in primary islets. While, tauroursodeoxycholic acid (TUDCA), an inhibitor of ER stress, significantly attenuated NMDA-induced β-cell dysfunction, including the loss of glucose-stimulated insulin secretion and reduction of pancreas duodenum homeobox factor-1 (Pdx-1) mRNA expression, a transcription factor regulating insulin synthesis. Besides, NMDA-induced ER stress strongly promoted pro-inflammatory cytokines synthesis (IL-1β and TNF-α) in β cells. Interestingly, knockdown of CHOP attenuated β-cell dysfunction evoked by NMDA. Furthermore, we demonstrated that blockade of NMDARs ameliorated high-glucose-induced ER stress in vitro and in vivo.This study confirms that ER stress is actively involved in the activation of NMDARs-related β-cell dysfunction.
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