Mizagliflozin inhibits proliferation and fibrosis of autosomal dominant polycystic kidney cells by inhibiting function of sodium-glucose cotransporter 1
10.16781/j.CN31-2187/R.20240144
- VernacularTitle:米扎格列净通过抑制钠-葡萄糖共转运体1的功能抑制常染色体显性多囊肾细胞增殖和纤维化
- Author:
Wenyu LIU
1
,
2
;
Shuangcheng WU
;
Tianchen ZHANG
;
Lili FU
;
Liangyu XIE
;
Wanqian HU
;
Shengqiang YU
Author Information
1. 海军军医大学(第二军医大学)第二附属医院肾脏病科,上海 200003
2. 中国人民解放军联勤保障部队北戴河康复疗养中心肾脏病科,秦皇岛 066000
- Keywords:
autosomal dominant polycystic kidney disease;
sodium-glucose cotransporter 1;
cell proliferation;
fibrosis;
phosphatidylinositol 3-kinase;
protein kinase B;
mitogen-activated protein kinase;
signaling pathway
- From:
Academic Journal of Naval Medical University
2024;45(11):1343-1351
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the role of sodium-glucose cotransporter 1(SGLT1)inhibitor mizagliflozin(MIZA)in autosomal dominant polycystic kidney disease(ADPKD).Methods Western blotting,quantitative polymerase chain reaction(qPCR),and immunofluorescence staining were used to determine the expression and distribution of SGLT1 in kidney tissues of PKD1-/-and PKD1+/+mice,human renal cancer adjacent tissue and ADPKD tissue.Renal cyst lining epithelial cells OX161 and renal tubular epithelial cells UCL93 were treated with MIZA,incubated at 37℃for 24,48,and 72 h,and then were subjected to methyl thiazolyl tetrazolium and colony formation assay to observe cell proliferation.The qPCR method was used to determine the mRNA levels of collagen 1α1,collagen 3α1,and fibronectin 1 in OX161 cells treated with 100 μmol/L MIZA for 48 h.The Madin-Darby canine kidney(MDCK)cell 3D cyst formation assay verified the effect of MIZA on cyst formation.The mRNA-seq technology was used to detect differentially expressed genes between UCL93 cells and OX161 cells,and between OX161 cells and OX161 cells treated with 100 μmol/L MIZA for 48 h,and then the differentially expressed genes were analyzed with Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.Results The expression level of SGLT1 was significantly increased in the tissues of ADPKD patients and PKD1-/-mice compared to those in normal kidney tissues(P＜0.05,P＜0.01).Immunofluorescence staining revealed that SGLT1 was mainly expressed in the cystic lining epithelial cells.Additionally,MIZA inhibited the proliferation and fibrosis of polycystic kidney cells in a concentration-and time-dependent manner,and also inhibited cyst formation in 3D formation assay in vitro.The mRNA-seq analysis and KEGG enrichment analysis showed that differentially expressed genes between OX161 cells and OX161 cells cultured in 100 μmol/L MIZA for 48 h were mainly enriched in the phosphatidylinositol 3-kinase(PI3K)-protein kinase B(Akt)and mitogen-activated protein kinase(MAPK)signaling pathways,which were the same as those between OX161 cells and UCL93 cells.Conclusion The SGLT1 inhibitor MIZA may inhibit the proliferation and fibrosis of polycystic kidney cells through signaling pathways such as PI3K-Akt and MAPK,delaying the growth of polycystic kidney,and it is a potential therapeutic target for ADPKD.
