Upregulation of α-ENaC induces pancreatic β-cell dysfunction,ER stress,and SIRT2 degradation  

作　　者：Xue Zhang Dan Zhang Lei Huo Xin Zhou Jia Zhang Min Li Dongming Su Peng Sun Fang Chen Xiubin Liang 

机构地区：[1]Department of Pathophysiology,Nanjing Medical University,Nanjing,Jiangsu 211166,China [2]Department of Pathology,Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing University Medical School,Nanjing,Jiangsu 210009,China [3]Key Laboratory of Human Functional Genomics of Jiangsu Province,Department of Biochemistry and Molecular Biology,Nanjing Medical University,Nanjing,Jiangsu 211166,China [4]Department of Pathology,Nanjing Medical University,Nanjing,Jiangsu 211166,China

出　　处：《Journal of Biomedical Research》2024年第3期241-255,共15页生物医学研究杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant Nos.81870467 and 82270717 to XL,and 81970673 to FC);China Postdoctoral Science Foundation(Grant No.2023M731630 to XZhang);Postgraduate Research and Practice Innovation Program of Jiangsu Province(Grant No.KYCX21_1588 to XZhou).

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 inβ-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 theβ-cells.In the current study,we found thatα-ENaC was expressed in human pancreatic glandule and pancreatic isletβ-cells.In the pancreas of db/db mice and high-fat diet-induced mice,and in mouse isletβ-cells(MIN6 cells)treated with palmitate,α-ENaC expression was increased.Whenα-ENaC was overexpressed in MIN6 cells,insulin content and glucose-induced insulin secretion were significantly reduced.On the other hand,palmitate injured isletβ-cells and suppressed insulin synthesis and secretion,but increasedα-ENaC expression in MIN6 cells.However,α-ENaC knockout(Scnn1a−/−)in MIN6 cells attenuatedβ-cell disorder induced by palmitate.Furthermore,α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 inβ-cells.α-ENaC also modulatedβ-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 thatα-ENaC may play a novel role in insulin synthesis and secretion in theβ-cells,and the upregulation ofα-ENaC promotes isletβ-cell dysfunction.In conclusion,α-ENaC may be a key regulator involved in isletβ-cell damage and a potential therapeutic target for type 2 diabetes mellitus.

关 键 词：α-ENaC pancreaticβ-cells type 2 diabetes mellitus endoplasmic reticulum stress sirtuin 2 

分 类 号：R587.1[医药卫生—内分泌]