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Telmisartan Mitigates High-Glucose-Induced Injury in Renal Glomerular Endothelial Cells (rGECs) and Albuminuria in Diabetes Mice
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2021-08-31 , DOI: 10.1021/acs.chemrestox.1c00159
Xiaolin Zhan 1 , Wei Chen 2 , Jian Chen 1 , Changjiang Lei 3 , Liqin Wei 1
Affiliation  

Diabetic nephropathy (DN) is a common and severe complication of diabetes, impacting millions of people worldwide. High concentrations of serum glucose-associated injury of renal glomerular endothelial cells (rGECs) are involved in the DN pathogenesis. We found that exposure to high glucose increased the expression of angiotensin II type 1 receptor (AT1R) in human rGECs (hrGECs). To block the increased AT1R level, we used the newly developed antagonist Telmisartan. This study investigated whether Telmisartan possessed a beneficial effect against high-glucose-induced insults in hrGECs and explored the underlying mechanism. Our findings indicate that Telmisartan ameliorated high-glucose-induced mitochondrial dysfunction by increasing mitochondrial membrane potential. Also, Telmisartan attenuated oxidative stress by reducing the levels of two oxidative stress biomarkers 8-hydroxy-2 deoxyguanosine (8-OHDG) and malondialdehyde (MDA). Further, we found that Telmisartan prevented high-glucose-induced expression of NADPH oxidase 2 (NOX-2). Interestingly, exposure to high glucose resulted in the increased endothelial permeability of renal glomerular endothelial cells, which was mitigated by treatment with Telmisartan. Mechanistically, these effects are mediated by the MLCK/MLC-2/occludin signaling pathway. In the leptin-deficient db/db diabetic mouse model, we proved that Telmisartan treatment ameliorated the reduction of occludin and albuminuria. In conclusion, our findings demonstrate that Telmisartan possesses protective effects on high-glucose-induced injury to renal glomerular endothelial cells; its antagonizing of AT1R could be a potential therapeutic target in diabetic nephropathy.

中文翻译:

替米沙坦减轻糖尿病小鼠肾小球内皮细胞 (rGEC) 和白蛋白尿的高葡萄糖损伤

糖尿病肾病 (DN) 是一种常见且严重的糖尿病并发症,影响着全球数百万人。肾小球内皮细胞 (rGEC) 的高浓度血清葡萄糖相关损伤与 DN 发病机制有关。我们发现暴露于高葡萄糖会增加人 rGECs (hrGECs) 中血管紧张素 II 1 型受体 (AT1R) 的表达。为了阻止增加的 AT1R 水平,我们使用了新开发的拮抗剂替米沙坦。本研究调查了替米沙坦是否对高糖诱导的 hrGEC 损伤具有有益作用,并探讨了其潜在机制。我们的研究结果表明,替米沙坦通过增加线粒体膜电位来改善高糖诱导的线粒体功能障碍。还,替米沙坦通过降低两种氧化应激生物标志物 8-羟基-2 脱氧鸟苷 (8-OHDG) 和丙二醛 (MDA) 的水平来减轻氧化应激。此外,我们发现替米沙坦阻止高糖诱导的 NADPH 氧化酶 2 (NOX-2) 的表达。有趣的是,暴露于高糖导致肾小球内皮细胞的内皮通透性增加,而替米沙坦治疗可减轻这种情况。从机制上讲,这些效应是由 MLCK/MLC-2/occludin 信号通路介导的。在缺乏瘦素的 db/db 糖尿病小鼠模型中,我们证明替米沙坦治疗改善了 occludin 和白蛋白尿的减少。总之,我们的研究结果表明,替米沙坦对高糖诱导的肾小球内皮细胞损伤具有保护作用;
更新日期:2021-09-20
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