Skeletal muscle insulin resistance in salt-sensitive hypertension: role of angiotensin II activation of NFκB.
Skeletal muscle insulin resistance in salt-sensitive hypertension: role of angiotensin II activation of NFκB.
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盐敏感性高血压中的骨骼肌胰岛素抵抗：血管紧张素 II 激活 NFkB 的作用
DOI：
10.1186/s12933-015-0211-6
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发表时间：
2015-05-01
影响因子：
9.3
通讯作者：
Raij L
中科院分区：
文献类型：
--
作者：
Zhou MS;Liu C;Tian R;Nishiyama A;Raij L
我们先前已经证明，高血压Dahl盐敏感(DS)大鼠对乙酰胆碱和胰岛素的内皮依赖性松弛受损与血管紧张素II(Ang II)活性上调和活性氧自由基(ROS)的产生以及促炎转录因子(NF)κB的激活有关。在此，我们研究了该动物模型骨骼肌中血管紧张素IIκB的激活是否参与了胰岛素抵抗。DS大鼠按正常(生理盐水，0.5%氯化钠)或高盐(HS，4%氯化钠)饮食喂养6周。此外，3组HS大鼠分别给予血管紧张素受体1阻滞剂坎地沙坦(饮用水中10 mg/kg/天)、抗氧化剂坦普尔(饮用水中1 mg/kg)或核因子κB抑制剂PDTC(饮用水中150 mg/kg)。DS大鼠比目鱼肌Ang II含量、ROS生成量和磷酸化IκBα/IκBα比值增加，Arb或Temol降低ROS和磷酸化IκBα/IκBα比值。高血压DS大鼠还表现出葡萄糖输注速率降低，胰岛素诱导的Akt磷酸化和比目鱼肌GLUT-4移位受损，这些都可以通过ARB、Tempoll或PDTC的治疗来预防。大鼠糖尿病信号通路基因芯片的数据显示，在84个靶基因中，有8个基因在高血压大鼠的肌肉中发生了改变，其中ACE1和5个促炎基因的基因表达增加，2个糖代谢基因的表达减少。将肌肉与NFκBSN50(一种NFκB的特异性多肽抑制剂)体外孵育，逆转了高血压诱导的基因表达的变化。目前的研究结果有力地表明，血管紧张素Ⅱ激活的NF-κ-B炎症通路在盐敏感型高血压骨骼肌胰岛素抵抗中起重要作用。
We have previously shown that in hypertensive Dahl salt-sensitive (DS) rats, impaired endothelium-dependent relaxation to acetylcholine and to insulin is mechanistically linked to up-regulation of angiotensin (Ang) II actions and the production of reactive oxygen species (ROS) and to activation of the proinflammatory transcription factor (NF)κB. Here we investigated whether Ang II activation of NFκB contributed to insulin resistance in the skeletal muscle of this animal model. DS rats were fed either a normal (NS, 0.5% NaCl) or high (HS, 4% NaCl) salt diet for 6 weeks. In addition, 3 separate groups of HS rats were given angiotensin receptor 1 blocker candesartan (ARB, 10 mg/kg/day in drinking water), antioxidant tempol (1 mmol/L in drinking water) or NFκB inhibitor PDTC (150 mg/kg in drinking water). DS rats manifested an increase in soleus muscle Ang II content, ROS production and phosopho-IκBα/IκBα ratio, ARB or tempol reduced ROS and phospho-IκBα/IκBα ratio. Hypertensive DS rats also manifested a reduction in glucose infusion rate, impaired insulin-induced Akt phosphorylation and Glut-4 translocation in the soleus muscle, which were prevented with treatment of either ARB, tempol, or PDTC. Data from the rat diabetes signaling pathway PCR array showed that 8 genes among 84 target genes were altered in the muscle of hypertensive rats with the increase in gene expression of ACE1 and 5 proinflammatory genes, and decrease of 2 glucose metabolic genes. Incubation of the muscle with NFκB SN50 (a specific peptide inhibitor of NFκB) ex vivo reversed changes in hypertension-induced gene expression. The current findings strongly suggest that the activation of NFκB inflammatory pathway by Ang II play a critical role in skeletal muscle insulin resistance in salt-sensitive hypertension.
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