Empagliflozin protects diabetic pancreatic tissue from damage by inhibiting the activation of the NLRP3/caspase-1/GSDMD pathway in pancreatic β cells: in vitro and in vivo studies

被引:26
作者
Liu, Pan [1 ,2 ]
Zhang, Zhengdong [1 ,3 ]
Wang, Jinwu [4 ]
Zhang, Xiao [1 ,2 ]
Yu, Xiaoping [5 ]
Li, Yao [1 ,2 ]
机构
[1] Chengdu Med Coll, Sch Clin Med, Chengdu 610500, Peoples R China
[2] Chengdu Med Coll, Affiliated Hosp 1, Dept Endocrinol, Chengdu, Peoples R China
[3] Chengdu Med Coll, Affiliated Hosp 1, Dept Orthoped, Chengdu, Peoples R China
[4] Chengdu Med Coll, Sch Biosci & Technol, Chengdu, Peoples R China
[5] Chengdu Med Coll, Sch Publ Hlth, Chengdu, Peoples R China
基金
中国国家自然科学基金;
关键词
Empagliflozin; pancreatic beta cells; NLRP3; caspase-1; GSDMD; MOLECULAR-MECHANISMS; INFLAMMASOME; STRESS; DYSFUNCTION; PREVENTION; PYROPTOSIS; OBESITY; DEATH;
D O I
10.1080/21655979.2021.2001240
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Diabetes mellitus is an important public health problem worldwide. Insulin deficiency caused by pancreatic beta cell dysfunction is an important pathogenic factor of diabetes mellitus. This study evaluated whether empagliflozin (EMPA) protects the pancreas from diabetes mellitus-induced injury by downregulating the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)/caspase-1/Gasdermin D (GSDMD) pyroptosis-related inflammasome pathway in vitro and in vivo. In vivo, animals were separated into blank control (control, C57/bl6j wild-type mice), diabetes model (db/db mice, BKS-Lepr(em2Cd479)/Gpt mice), and db/db mice+EMPA (db/db+EMPA) groups. In vitro, pancreatic beta cells were separated into low glucose (control), high glucose (HG), and HG+EMPA groups. The db/db+EMPA group were administered empagliflozin at 10 mg/(kg.day) by gavage for six months. Histological changes in the pancreatic tissues were observed by hematoxylin-eosin staining, and levels of the pyroptosis-related inflammatory factors NLPR3, caspase-1, and GSDMD were measured by immunohistochemistry and immunofluorescence staining methods. The Cell Counting Kit-8 assay was used to detect the effect of different concentrations of glucose and empagliflozin on the proliferation of mouse insulinoma islet beta (beta TC-6) cells. NLRP3/caspase-1/GSDMD expression was assessed by western blotting and immunofluorescent labeling in the beta TC-6 cells. The results showed that empagliflozin reduced the pathological changes and inflammatory cell infiltration in the pancreatic tissues of db/db mice. Furthermore, empagliflozin not only reduced the expression levels of NLRP3/caspase-1/GSDMD in vitro, but also reduced their expression levels in vivo. In summary, our data suggested that empagliflozin protects the pancreatic tissues from diabetes mellitus-induced injury by downregulating the NLRP3/caspase-1/GSDMD pyroptosis-related inflammasome pathway. [GRAPHICS] .
引用
收藏
页码:9356 / 9366
页数:11
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