Metabolic Syndrome Induces Over Expression of the Human AT1R: A Haplotype-Dependent Effect With Implications on Cardio-Renal Function.
Metabolic Syndrome Induces Over Expression of the Human AT1R: A Haplotype-Dependent Effect With Implications on Cardio-Renal Function.
复制标题
代谢综合征诱导人类 AT1R 过度表达：单倍型依赖性效应，对心肾功能有影响。
DOI：
10.1093/ajh/hpx176
复制
发表时间：
2018
影响因子：
3.2
通讯作者：
Kumar,Ashok
中科院分区：
文献类型：
--
作者：
Jain,Sudhir;Puri,Nitin;Rana,Anita;Sirianni,Natalie;Mopidevi,Brahmaraju;Kumar,Ashok
背景人类血管紧张素受体亚型1（AT 1 R）基因在病理生理学（如代谢综合征）中的转录调控知之甚少。人类AT 1 R基因在其启动子中具有多态性，可以排列成2种单倍型。变体-810T、-713T、-214A和-153A总是一起出现（Hap-I），变体-810A、-713G、-214C和-153G形成Hap-II。我们假设高脂饮食会改变细胞的转录环境，并以单倍型依赖的方式增加hAT 1 R基因的表达。这将建立一个AT 1 R介导的前馈环，促进炎症，氧化应激，高血压Hap-I mice. METHODS由于Hap-I的人类AT 1 R基因与高血压在高加索人，我们产生转基因（TG）小鼠Hap-I和Hap-II和研究的生理意义，高脂饮食（HFD）的单倍型特异性基因表达。用HFD喂养动物20周，然后进行血压（BP）分析并收集组织进行分子和生化研究。结果HFD治疗后，与Hap-II相比，Hap-I的TG小鼠表现出hAT 1 R基因表达增加和血压升高;抑制抗氧化防御体内ChIP实验显示，转录因子CEBPβ、STAT 3、结论HFD治疗后，与Hap-II相比，Hap-I的TG小鼠由于其更强的转录活性而过度表达AT 1 R基因，从而导致其BP升高。
BACKGROUNDThe transcriptional regulation of the human angiotensin receptor subtype 1 (AT1R) gene in pathophysiologies, like the metabolic syndrome, is poorly understood. The human AT1R gene has polymorphisms in its promoter that can be arranged in 2 haplotypes. Variants -810T, -713T, -214A, and -153A always occur together (Hap-I) and variants -810A, -713G, -214C, and -153G form Hap-II. We have hypothesized that high fat diet will alter cellular transcriptional milieu and increase hAT1R gene expression in a haplotype-dependent manner. This will set up an AT1R-mediated feed-forward loop promoting inflammation, oxidative stress, and hypertension in Hap-I mice.METHODSince Hap-I of the human AT1R gene is associated with hypertension in Caucasians, we generated transgenic (TG) mice with Hap-I and Hap-II and studied the physiological significance of high fat diet (HFD) on haplotype specific gene expression. Animals were fed with HFD for 20 weeks followed by blood pressure (BP) analysis and collection of their tissues for molecular and biochemical studies.RESULTSAfter HFD treatment, as compared to Hap-II, TG mice with Hap-I show increased expression of hAT1R gene and higher BP; suppression of antioxidant defenses (HO1, SOD1) and increased expression of IL-6, TNFα, IL-1β, NOX1.In vivoChIP assay has shown that transcription factors CEBPβ, STAT3, and USF bind more strongly to the chromatin obtained from Hap-I TG mice.CONCLUSIONSTaken together, our results suggest, that after HFD treatment, as compared to Hap-II, the TG mice with Hap-I overexpress the AT1R gene due to the stronger transcriptional activity, thus resulting in an increase in their BP.