The role of soluble prorenin receptor in hypertension associated with obesity

可溶性肾素原受体在肥胖相关高血压中的作用

• 批准号: 10198022
• 负责人: Analia Loria
• 金额: $ 38.08万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198022
• 关键词: 3T3-L1 Cells; Adipose tissue; Adrenergic Receptor; Affect; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Antihypertensive Agents; Binding; Biological Markers; Blood Pressure; Body Fluids; C57BL/6 Mouse; Calcium Channel Blockers; Cardiovascular Diseases; Cause of Death; Cell secretion; Cells; Chronic; Cleaved cell; Complex; Data; Diet; Drug usage; Fat-Restricted Diet; Fatty acid glycerol esters; Fluid Balance; Genes; Goals; HepG2; Hepatic; High Fat Diet; Human; Hypertension; In Vitro; Incubated; Infusion procedures; Kidney; Knockout Mice; Liver; Losartan; Mediating; Molecular; Mus; Obese Mice; Obesity; Obesity Epidemic; Outcome; Outcome Study; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Plasma; Population; Prevalence; Production; Recombinants; Renin; Renin-Angiotensin System; Resistant Hypertension; Risk; Role; Severities; Testing; Therapeutic; Tissues; Transcriptional Regulation; Transgenic Mice; United States; Urine; Vasoconstrictor Agents; Vasopressins; Work; antidiuretic; blood pressure regulation; cardiovascular risk factor; hypertension treatment; in vivo; insight; mortality; mouse model; nectin; neutralizing antibody; normotensive; novel; prevent; promoter; prorenin receptor; receptor; response; urinary

PROJECT SUMMARY/ABSTRACT The epidemic of obesity, currently affecting more than 36.5% of the population in the United States, has contributed to a rise in the prevalence of hypertension. We recently found that obesity stimulated the secretion of the soluble form of the prorenin receptor (PRR), sPRR, into plasma. While examining sPRR protein concentrations in tissues, we found an increase of sPRR protein levels in the liver, the adipose tissue and the kidney of control mice fed a high fat diet compared to mice fed a low fat diet. New preliminary data showed that the infusion of a recombinant mouse sPRR in mice fed a standard diet activated local and circulating RAS by increasing renal cortical angiotensinogen (AGT) and circulating renin levels. Consistent with those results, our new results demonstrated that elevated plasma sPRR in adipose PRR KO mice is associated with an increase of cortical angiotensin II levels in the kidney. Urinary vasopressin levels also increased significantly in these mice. Together with our prior work, these results raise the possibility that sPRR regulates the renin angiotensin system (RAS) and body fluid volume. To test this idea, 3T3-L1 cells and human HepG2 cells were incubated with increased concentration of recombinant mouse sPRR. We found that sPRR increased the expression of AGT gene in 3T3-L1 cells and the secretion of AGT in the media of human HepG2. In addition, the incubation with our sPRR neutralizing antibody decreased AngII levels in the media of 3T3-L1 cells. Because sPRR infusion in mice increased plasma renin levels, we also investigated whether sPRR regulated the expression of renin in kidney. Interestingly, we found that sPRR binds to the promoter of the renin gene. Thus, we propose that obesity stimulates sPRR production leading to hypertension through a mechanism that involves the activation of the RAS and increases AVP. We will test the hypothesis that tissue-derived sPRR mediates angiotensin II-induced hypertension associated with obesity, likely by amplifying the local AGT and renin response and increases urinary AVP. We will also investigate whether blocking sPRR can be used as a treatment for hypertension associated with obesity. Outcomes will demonstrate whether obesity is regulated through a previously unrecognized pathway represented by upstream control of RAS and AVP by sPRR. Our studies point to a unique functional role for sPRR in hypertension associated with obesity.

项目概要/摘要 肥胖症的流行，目前影响着超过 36.5% 的美国人口 州，导致高血压患病率上升。我们最近发现 肥胖刺激可溶性肾素原受体 (PRR) sPRR 的分泌 等离子体。在检查组织中 sPRR 蛋白浓度时，我们发现 喂食高脂肪的对照小鼠的肝脏、脂肪组织和肾脏中的 sPRR 蛋白水平 饮食与低脂饮食喂养的小鼠进行比较。新的初步数据表明，输注 喂食标准饮食的小鼠中的重组小鼠 sPRR 通过以下方式激活局部和循环 RAS： 增加肾皮质血管紧张素原（AGT）和循环肾素水平。符合 这些结果，我们的新结果表明，脂肪 PRR KO 中血浆 sPRR 升高 小鼠肾脏中皮质血管紧张素 II 水平的增加与此相关。泌尿 这些小鼠的加压素水平也显着增加。与我们之前的工作一起，这些 结果提出了 sPRR 调节肾素血管紧张素系统 (RAS) 和身体的可能性 液体体积。为了测试这个想法，将 3T3-L1 细胞和人 HepG2 细胞与 重组小鼠 sPRR 浓度增加。我们发现 sPRR 增加了 3T3-L1细胞中AGT基因的表达及人培养基中AGT的分泌 HepG2。此外，与我们的 sPRR 中和抗体一起孵育可降低 AngII 水平 在 3T3-L1 细胞的培养基中。由于小鼠体内 sPRR 输注增加了血浆肾素水平，我们 还研究了 sPRR 是否调节肾脏中肾素的表达。有趣的是，我们 发现 sPRR 与肾素基因的启动子结合。因此，我们建议肥胖 刺激 sPRR 产生，通过涉及以下机制导致高血压 激活 RAS 并增加 AVP。我们将检验以下假设：组织源性 sPRR 介导血管紧张素 II 诱导的与肥胖相关的高血压，可能是通过放大 局部 AGT 和肾素反应并增加尿 AVP。我们还将调查是否 阻断 sPRR 可用于治疗与肥胖相关的高血压。结果 将证明肥胖是否是通过以前未被识别的途径进行调节的 以sPRR对RAS和AVP的上游控制为代表。我们的研究指出了一个独特的 sPRR 在肥胖相关高血压中的功能作用。

项目成果

Adipose-derived human soluble (pro)renin receptor causes resistance to Losartan treatment in high-fat diet male and female mice.

脂肪来源的人可溶性肾素（原）受体导致高脂肪饮食的雄性和雌性小鼠对氯沙坦治疗产生抵抗。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Nichols,Kellea;Arthur,Gertrude;Hinds,Terry;Yiannikouris,Frederique
• 通讯作者: Yiannikouris,Frederique