Effects of SGLT2 inhibition in human kidney proximal tubular cells--renoprotection in diabetic nephropathy?
Effects of SGLT2 inhibition in human kidney proximal tubular cells--renoprotection in diabetic nephropathy?
复制标题
DOI：
10.1371/journal.pone.0054442
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mather A
中科院分区：
文献类型：
--
作者：
Panchapakesan U;Pegg K;Gross S;Komala MG;Mudaliar H;Forbes J;Pollock C;Mather A
钠/葡萄糖协同转运蛋白2（SGLT 2）抑制剂是用于治疗糖尿病患者的口服降糖药。SGLT 2抑制剂通过抑制SGLT 2（近端肾小管细胞（PTC）中的主要葡萄糖转运蛋白）阻断滤过葡萄糖的重吸收，导致糖尿和血糖降低。我们检查了SGLT 2抑制剂恩格列净的肾脏保护作用，以确定阻断葡萄糖进入肾脏PTC是否减少细胞对高糖的炎症和纤维化反应。我们使用人PTC的体外模型。在存在和不存在恩格列净的情况下，将HK 2细胞（人肾PTC系）暴露于对照5 mM、高浓度葡萄糖（HG）30 mM或促纤维化细胞因子转化生长因子β（TGFβ1; 0.5 ng/ml）长达72 h。评估SGLT 1和2表达以及各种炎症/纤维化标志物。染色质免疫沉淀试验用于确定磷酸化Smad 3与SGLT 2基因启动子区的结合。我们的数据显示，TGFβ1而非HG增加SGLT 2表达，这是通过磷酸化smad 3发生的。HG诱导Toll样受体-4的表达，增加核脱氧核糖核酸与核因子κ B（NF-κB）和激活蛋白1的结合，诱导IV型胶原蛋白表达以及白细胞介素-6分泌，所有这些都被恩格列净减弱。恩格列净未降低高迁移率族蛋白1诱导的NF-κB，表明其作用与糖毒性降低特异性相关。HG或恩格列净未显著改变SGLT 1和GLUT 2表达。总之，恩格列净通过阻断葡萄糖转运减少HG诱导的炎症和纤维化标志物，且未诱导SGLT 1/GLUT 2表达代偿性增加。尽管HG本身在我们的模型中不调节SGLT 2的表达，但TGFβ通过磷酸化smad 3增加SGLT 2的表达。
Sodium/glucose cotransporter 2 (SGLT2) inhibitors are oral hypoglycemic agents used to treat patients with diabetes mellitus. SGLT2 inhibitors block reabsorption of filtered glucose by inhibiting SGLT2, the primary glucose transporter in the proximal tubular cell (PTC), leading to glycosuria and lowering of serum glucose. We examined the renoprotective effects of the SGLT2 inhibitor empagliflozin to determine whether blocking glucose entry into the kidney PTCs reduced the inflammatory and fibrotic responses of the cell to high glucose. We used an in vitro model of human PTCs. HK2 cells (human kidney PTC line) were exposed to control 5 mM, high glucose (HG) 30 mM or the profibrotic cytokine transforming growth factor beta (TGFβ1; 0.5 ng/ml) in the presence and absence of empagliflozin for up to 72 h. SGLT1 and 2 expression and various inflammatory/fibrotic markers were assessed. A chromatin immunoprecipitation assay was used to determine the binding of phosphorylated smad3 to the promoter region of the SGLT2 gene. Our data showed that TGFβ1 but not HG increased SGLT2 expression and this occurred via phosphorylated smad3. HG induced expression of Toll-like receptor-4, increased nuclear deoxyribonucleic acid binding for nuclear factor kappa B (NF-κB) and activator protein 1, induced collagen IV expression as well as interleukin-6 secretion all of which were attenuated with empagliflozin. Empagliflozin did not reduce high mobility group box protein 1 induced NF-κB suggesting that its effect is specifically related to a reduction in glycotoxicity. SGLT1 and GLUT2 expression was not significantly altered with HG or empagliflozin. In conclusion, empagliflozin reduces HG induced inflammatory and fibrotic markers by blocking glucose transport and did not induce a compensatory increase in SGLT1/GLUT2 expression. Although HG itself does not regulate SGLT2 expression in our model, TGFβ increases SGLT2 expression through phosphorylated smad3.
登录
查看更多内容
影响因子：
120.7
作者：
de Boer, Ian H.;Rue, Tessa C.;Hall, Yoshio N.;Heagerty, Patrick J.;Weiss, Noel S.;Himmelfarb, Jonathan
通讯作者：
Himmelfarb, Jonathan
影响因子：
3.2
作者：
Vallon V;Sharma K
通讯作者：
Sharma K
影响因子：
7.7
作者：
Sharma, K;Ziyadeh, FN;Weisberg, LS
通讯作者：
Weisberg, LS
影响因子：
15.9
作者：
ZIYADEH, FN;SHARMA, K;WOLF, G
通讯作者：
WOLF, G
影响因子：
168.9
作者：
Bailey, Clifford J.;Gross, Jorge L.;List, James F.
通讯作者：
List, James F.