Upregulation of α-ENaC induces pancreatic β-cell dysfunction,ER stress,and SIRT2 degradation
Xue Zhang1
Dan Zhang1
Lei Huo2
Xin Zhou2
Jia Zhang3
Min Li4
Dongming Su4
Peng Sun3
Fang Chen3
Xiubin Liang2
1.Department of Pathophysiology,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Department of Pathology,Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing University Medical School,Nanjing,Jiangsu 210009,China2.Department of Pathophysiology,Nanjing Medical University,Nanjing,Jiangsu 211166,China3.Key Laboratory of Human Functional Genomics of Jiangsu Province,Department of Biochemistry and Molecular Biology,Nanjing Medical University,Nanjing,Jiangsu 211166,China4.Department of Pathology,Nanjing Medical University,Nanjing,Jiangsu 211166,China
摘要：Islet beta cells(β-cells)produce insulin in response to high blood glucose levels,which is essential for preserving glucose homeostasis.Voltage-gated ion channels in β-cells,including Na+,K+,and Ca2+channels,aid in the release of insulin.The epithelial sodium channel alpha subunit(α-ENaC),a voltage-independent sodium ion channel,is also expressed in human pancreatic endocrine cells.However,there is no reported study on the function of ENaC in the β-cells.In the current study,we found that α-ENaC was expressed in human pancreatic glandule and pancreatic islet β-cells.In the pancreas of db/db mice and high-fat diet-induced mice,and in mouse islet β-cells(MIN6 cells)treated with palmitate,α-ENaC expression was increased.When α-ENaC was overexpressed in MIN6 cells,insulin content and glucose-induced insulin secretion were significantly reduced.On the other hand,palmitate injured islet β-cells and suppressed insulin synthesis and secretion,but increased α-ENaC expression in MIN6 cells.However,α-ENaC knockout(Scnn1a-/-)in MIN6 cells attenuated β-cell disorder induced by palmitate.Furthermore,α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 in β-cells.α-ENaC also modulated β-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1(IRE1α/XBP1)and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein(PERK/CHOP)endoplasmic reticulum stress pathways.These results suggest that α-ENaC may play a novel role in insulin synthesis and secretion in the β-cells,and the upregulation of α-ENaC promotes islet β-cell dysfunction.In conclusion,α-ENaC may be a key regulator involved in islet β-cell damage and a potential therapeutic target for type 2 diabetes mellitus.
机标关键词：degradationstresssirt2enaccelldysfunctioninducespancreatic
分类号：R587.1(内分泌腺疾病及代谢病)
论文发表日期：2024-05-30
在线出版日期：2026-03-31（本平台首次上网日期，不代表文献的发表时间）
页数：16( 中插5,241-255 )
英文信息