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坎地沙坦抑制脂多糖诱导的toll样受体4及下游炎症因子的表达增加——不依赖血管紧张素II 1型受体

赵莉芹, 黄洁丽, 余莹, 陆英, 傅兰君, 王均玲, 王艳道, 余晨

同济大学附属同济医院肾脏科，上海 200065；同济大学附属东方医院中心实验室，上海 200120

摘要

本文旨在离体培养人肾小管上皮细胞株(human renal tubular epithelial cells, HKCs)上研究血管紧张素II 1型受体阻断剂(angiotensin II type 1 receptor blocker, ARB)坎地沙坦抗炎效应的机制。用流式细胞仪、Western blot、RT-PCR和ELISA技术分别检测HKCs的toll样受体4 (toll-like receptor 4, TLR4)蛋白水平、血管紧张素II 1型受体(angiotensin II type 1 receptor, AT1R)和磷酸化核因子-κB (nuclear factor-kappa B, NF-κB) p65蛋白、巨噬细胞趋化蛋白-1 (macrophage chemoattractant protein-1, MCP-1)和RANTES的mRNA水平，以及MCP-1和RANTES在培养液中的蛋白浓度。结果显示，在离体培养的HKCs中，脂多糖(lipopolysaccharide, LPS)上调TLR4蛋白表达水平，增强NF-κB活化和下游炎症因子(包括MCP-1和RANTES)释放；坎地沙坦逆转LPS引起的TLR4表达的上调、NF-κB活化及MCP-1和RANTES的释放，但用siRNA下调AT1R表达并不改变坎地沙坦的这些效应。以上结果提示，坎地沙坦通过一条新的不依赖于AT1R的途径发挥抗炎效应。

关键词： TLR4; LPS; 血管紧张素 II1型受体阻断剂; NF-κB; 炎症

分类号：R34

Candesartan inhibits LPS-induced expression increase of toll-like receptor 4 and downstream inflammatory factors likely via angiotensin II type 1 receptor independent pathway in human renal tubular epithelial cells

ZHAO Li-Qin, HUANG Jie-Li, YU Ying, Lu Ying, FU Lan-Jun, WANG Jun-Ling, WANG Yan-Dao, YU Chen

Division of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China； Department of Nephrology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China

Abstract

The present study was to determine whether candesartan, an angiotensin II type 1 receptor blocker (ARB), exerts anti-inflammatory effects through inhibiting the toll-like receptor 4 (TLR4) pathway in human renal tubular epithelial cells (HKCs). The experiments were carried on cultured HKCs. By means of flow cytometry, Western blot, RT-PCR and ELISA techniques, the TLR4 protein, angiotensin II type 1 receptor (AT1R) and phosphorylated nuclear factor-kappa B (NF-κB) p65 protein level, mRNA levels of macrophage chemoattractant protein-1 (MCP-1) and regulated upon expression normal T cell expressed and secreted (RANTES), as well as MCP-1 and RANTES protein concentrations in conditioned media were measured. The results showed that lipopolysaccharide (LPS) upregulated the TLR4 protein level in cultured HKCs. Application of LPS increased NF-κB activation and induced release of its downstream inflammatory factors including MCP-1 and RANTES. Candesartan reversed LPS-induced upregulation of TLR4 expression, inhibited NF-κB activation, and reduced MCP-1 and RANTES release. However, knockdown on AT1R by siRNA did not change those previous effects of candesartan. These results suggest that candesartan-induced anti-inflammatory effect may be through a novel pathway, independent of AT1R.

Key words: toll-like receptor 4; lipopolysaccharide; angiotensin II type 1 receptor blockers; NF-kappa B; inflammation

收稿日期：2013-04-23　　录用日期：2013-06-20

通讯作者：余晨　　E-mail: yuchen2001@hotmail.com

引用本文：

赵莉芹, 黄洁丽, 余莹, 陆英, 傅兰君, 王均玲, 王艳道, 余晨. 坎地沙坦抑制脂多糖诱导的toll样受体4及下游炎症因子的表达增加——不依赖血管紧张素II 1型受体[J]. 生理学报 2013; 65 (6): 623-630.

ZHAO Li-Qin, HUANG Jie-Li, YU Ying, Lu Ying, FU Lan-Jun, WANG Jun-Ling, WANG Yan-Dao, YU Chen. Candesartan inhibits LPS-induced expression increase of toll-like receptor 4 and downstream inflammatory factors likely via angiotensin II type 1 receptor independent pathway in human renal tubular epithelial cells. Acta Physiol Sin 2013; 65 (6): 623-630 (in Chinese with English abstract).