Effect of dapagliflozin on gene expression of glucose transporter 2 and glucose transporter 4 in kidney of type 2 diabetic rats

doi:10.12047/j.cjap.6001.2020.119

Abstract

Abstract: Objective: To investigate the effects of dapagliflozin on the gene expressions of glucose transporter 2 (GLUT2) and glucose transporter 4 (GLUT4) in type 2 diabetic rats. Methods: High fat diet and 40 mg/kg streptozotocin (STZ) were used to establish the rat model of type 2 diabetes mellitus. When the fasting blood glucose (FBG) content was more than or equal to 16.7 mmol/L, the model was established successfully. After successful modeling, the rats were randomly divided into model group (group B, normal saline), dapagliflozin low-dose group (Group C, 0.75 mg/kg), dapagliflozin middle dose group (Group D, 1.5 mg/kg) and dapagliflozin high-dose group (Group E, 3.0 mg/kg), with 6 rats in each group. Six healthy SD rats were selected as normal control group (group A, normal saline). Each group was administrated by gavage once a day for 7 weeks. The body weight, serum FBG, hemoglobin A1c (HbA1c), blood urea nitrogen (BUN) and serum creatinine (Scr) were measured after 7 weeks. The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in serum and kidney were measured by enzyme-linked immunosorbent assay (ELISA). HE staining was used to observe the pathological changes of kidney. The protein expressions of GLUT2 and GLUT4 were detected by Western blot. RT-qPCR was used to detect the relative expressions of GLUT2 and GLUT4 mRNA in kidney tissue. Results: Compared with group A, the body weight, SOD, GSH-Px levels of rats in each group were significantly decreased (P＜0.05), while the levels of FBG, HbA1c, BUN, SCR and MDA were significantly increased (P＜0.05), renal pathological damage was serious, the relative expressions of GLUT2, GLUT4 mRNA and protein in renal tissue were significantly decreased (P＜0.05). Compared with group B, the body weight, SOD, GSH-Px levels and the mRNA relative expressions of GLUT2 and GLUT4 in group C, group D and group E were significantly increased (P＜0.05), while the levels of FBG, HbA1c, BUN, SCR and MDA were significantly decreased (P＜0.05). The renal pathological damage in group D and group E was significantly alleviated, and the expressions of GLUT2 and GLUT4 protein in renal tissue were significantly increased (all P＜0.05). Conclusion: Dapagliflozin can alleviate the condition of type 2 diabetic rats and up regulate the expression of GLUT2 and GLUT4 genes in kidney.

Key words: dapagliflozin, type 2 diabetes mellitus, rats, GLUT2, GLUT4

CLC Number:

XU Yun, CHEN Xue-hui, BAI Li-wei, YIN Qing-feng, FENG Chun-yu, ZHANG Qing-gui. Effect of dapagliflozin on gene expression of glucose transporter 2 and glucose transporter 4 in kidney of type 2 diabetic rats[J]. CJAP, 2020, 36(6): 565-570.

References

[1] Jia W. Diabetes research in China: making progress[J]. Lancet Diabetes Endocrinol, 2017, 5(1): 9-10.
[2] Jeon HJ, Ku EJ, Oh TK. Dapagliflozin improves blood glucose in diabetes on triple oral hypoglycemic agents having inadequate glucose control[J]. Diabetes Res Clin Pract, 2018, 142: 188-194.
[3] Reyhaneh J, Mahbubeh S. The protective effect of Satureja bachtiarica hydroalcoholic extract on streptozotocin-induced diabetes through modulating glucose transporter 2 and 4 expression and inhibiting oxidative stress[J]. Pharm Biol, 2019, 57(1): 318-327.
[4] 刘美晓, 孙一婵, 侯丽娜, 等. 丝胶对2型糖尿病大鼠胰腺胰岛素PI3K-Akt信号通路的调节作用[J]. 解剖学报, 2016, 47(6): 807-811.
[5] 覃晓莉, 檀梦天, 洪艳. 葡萄糖转运蛋白2在人脐带间充质干细胞向胰岛前体细胞分化过程中表达的变化[J]. 解剖学报, 2017, 48(4): 410-415.
[6] 贾宇. 电针“足三里”、“肾俞”穴对T2DM大鼠GLUT2、GCK影响的实验研究[D]. 北京: 北京中医药大学, 2017.
[7] 史旭成, 田玉平, 杨晓荣. 达格列净对老年糖尿病患者的临床疗效及肾功能影响[J]. 山西医药杂志, 2019, 48(1): 82-84.
[8] 余维, 刘霞, 骆小华, 等. 慢性间歇性低氧对大鼠肾脏GLUT-2和IRS-2表达的影响[J]. 基础医学与临床, 2017, 37(2): 206-210.
[9] Liad H, Shiran U, Adi D, et al. Modulation of renal GLUT2 by the cannabinoid-1 receptor: Implications for the treatment of diabetic nephropathy[J]. J Am Soc Nephrol, 2018, 29(2): 434-448.
[10] Ayyasamy R, Leelavinothan P. Myrtenal ameliorates hyperglycemia by enhancing GLUT2 through Akt in the skeletal muscle and liver of diabetic rats[J]. Chem Biol Interact, 2016, 256: 161-166.
[11] 张薇. 内质网应激、钙调神经磷酸酶与原发性膜性肾病患者对环孢素治疗反应的相关性[D]. 北京: 北京协和医学院中国医学科学院, 2016.
[12] Mi J, He WD, Lv JW, et al. Effect of berberine on the HPA-axis pathway and skeletal muscle GLUT4 in type 2 diabetes mellitus rats[J]. Diabetes Metab Syndr Obes, 2019, 12: 1717-1725.
[13] 赵威, 蒙向欣, 李娟, 等. 加味芪黄饮激活InsR-IRS-1-PI3K-GLUT4信号通路延缓糖尿病肾病的研究[J]. 广东药科大学学报, 2020, 36(3): 375-380.
[14] 张环, 都敏, 张晶晶, 等. 2型糖尿病的治疗与GLUT4的关系[J]. 中国临床研究, 2013, 26(12): 1388-1389.
[15] Kang O, Shon M, Kong R, et al. Anti-diabetic effect of black ginseng extract by augmentation of AMPK protein activity and upregulation of GLUT2 and GLUT4 expression in db/db mice[J]. BMC Complement Altern Med, 2017, 17(1): 341-351.
[16] 安玉, 刘志红. 钠-葡萄糖共转运蛋白2抑制剂的代谢调控及心肾保护作用[J]. 肾脏病与透析肾移植杂志, 2018, 27(5): 457-462.
[17] 戚琛晔. 2型糖尿病大鼠氧化应激与骨骼肌细胞GLUT4表达及转位的相关性研究[D]. 河南: 河南科技大学, 2014.
[18] Verma S, Alam R, Ahmad I, et al. Effect of glycemic control and disease duration on cardiac autonomic function and oxidative stress in type 2 diabetes mellitus[J]. J Diabetes Metab Disord, 2018, 17(2): 149-158.
[19] Lv L, Li D, Tian F, et al. Silence of lncRNA GAS5 alleviates high glucose toxicity to human renal tubular epithelial HK-2 cells through regulation of miR-27a[J]. Artif Cells Nanomed Biotechnol, 2019, 47(1): 2205-2212.
[20] 铁丰红, 周男, 于磊. 钠-葡萄糖共转运蛋白2抑制剂改善2型糖尿病患者胰岛素抵抗的研究进展[J]. 中华糖尿病杂志, 2019, 11(4): 290-292.