Age-Related Expression of Human AT1R Variants and Associated Renal Dysfunction in Transgenic Mice.
Age-Related Expression of Human AT1R Variants and Associated Renal Dysfunction in Transgenic Mice.
复制标题
转基因小鼠中人类 AT1R 变体的年龄相关表达和相关肾功能障碍。
DOI：
10.1093/ajh/hpy121
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;Rana,Anita;Jain,Kavita;Perla,SravanK;Puri,Nitin;Kumar,Ashok
背景单核苷酸多态性在人类血管紧张素受体I型（hAT 1 R）基因转录调控中的作用在与年龄相关的慢性疾病如高血压和相关的肾脏疾病中的作用还不清楚。hAT 1 R基因在其启动子中具有单核苷酸多态性，形成2种单倍型（Hap），Hap-I和Hap-II。AT 1 R基因Hap-I与白种人高血压相关我们假设年龄会改变细胞的转录环境，并以单倍型依赖的方式调节hAT 1 R基因的表达。这可能使Hap-I受试者对年龄相关的AT 1 R介导的并发症越来越敏感。METHODWe产生了Hap-I和Hap-II转基因（TG）小鼠。成年人（10-12周）和年龄将20-24月龄的Hap-I或Hap-II转基因雄性小鼠分为4组，研究hAT 1 R基因的年龄相关性和单倍型特异性转录调控及其生理相关性。抑制抗氧化防御（血红素加氧酶、超氧化物歧化酶）和抗衰老分子（ATRAP，Klotho，Sirt 3）;促炎标志物表达增加（IL-6、TNFα、CRP、NOX 1）;体内ChIP检测显示转录因子USF 2与Hap-2细胞的染色质结合更强，结论与Hap-II型相比，Hap-I型TG小鼠hAT 1 R基因转录活性更强，在老年动物中hAT 1 R基因过表达，从而导致血压升高和相关的肾脏疾病。
BACKGROUNDThe contribution of single nucleotide polymorphisms in transcriptional regulation of the human angiotensin receptor type I (hAT1R) gene in age-related chronic pathologies such as hypertension and associated renal disorders is not well known. The hAT1R gene has single nucleotide polymorphisms in its promoter that forms 2 haplotypes (Hap), Hap-I and Hap-II. Hap-I of AT1R gene is associated with hypertension in Caucasians. We have hypothesized here that age will alter the transcriptional environment of the cell and will regulate the expression of hAT1R gene in a haplotype-dependent manner. This could likely make subjects with Hap-I increasingly susceptible to age-associated, AT1R-mediated complications.METHODWe generated transgenic (TG) mice with Hap-I and Hap-II. Adults (10–12 weeks) and aged (20–24 months) TG male mice containing either Hap-I or Hap-II were divided into 4 groups to study (i) the age-associated and haplotype-specific transcriptional regulation of hAT1R gene and (ii) their physiological relevance.RESULTSIn aged animals, TG mice with Hap-I show increased expression of hAT1R and higher blood pressure (BP); suppression of antioxidant defenses (hemoxygenase, superoxide dismutase) and antiaging molecules (ATRAP, Klotho, Sirt3); increased expression of pro-inflammatory markers (IL-6, TNFα, CRP, NOX1); and increased insulin resistance.In vivoChIP assay shows stronger binding of transcription factor USF2 to the chromatin of Hap-I mice.CONCLUSIONOur results suggest that in aged animals, as compared with Hap-II, the TG mice with Hap-I overexpress hAT1R gene due to the stronger transcriptional activity, thus resulting in an increase in their BP and associated renal disorders.