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.

项目总结/摘要 肥胖症的流行，目前影响着美国36.5%以上的人口， 在美国，导致高血压患病率上升。我们最近发现， 肥胖刺激了可溶性形式的前肾素受体（PRR）分泌，sPRR， 等离子体在检测组织中sPRR蛋白浓度时，我们发现 对照小鼠肝脏、脂肪组织和肾脏中sPRR蛋白水平 与喂食低脂肪饮食的小鼠相比。新的初步数据显示， 在喂食标准饮食的小鼠中，重组小鼠sPRR通过以下途径激活局部和循环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，在脂肪PRR KO中升高的血浆sPRR 小鼠的肾皮质血管紧张素II水平增加。尿 在这些小鼠中加压素水平也显著增加。加上我们以前的工作，这些 结果提示sPRR可能调节肾素血管紧张素系统（RAS）和机体 液体体积。为了测试这一想法，将3T3-L1细胞和人HepG2细胞与 增加重组小鼠sPRR的浓度。我们发现sPRR增加了 AGT基因在3T3-L1细胞中的表达及AGT在人细胞培养液中的分泌 HepG 2。此外，与我们的sPRR中和抗体孵育降低了AngII水平 在3T3-L1细胞的培养基中。由于小鼠输注sPRR增加了血浆肾素水平，我们 并研究了sPRR对肾脏中肾素表达的调节作用。有趣的是，我们 发现sPRR与肾素基因的启动子结合。因此，我们认为肥胖 刺激sPRR的产生，通过涉及 激活RAS并增加AVP。我们将检验组织源性sPRR 介导与肥胖相关的血管紧张素II诱导的高血压，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 阻断sPRR可用作与肥胖相关的高血压的治疗。成果 将证明肥胖是否是通过一个以前未被认识的途径来调节的 由sPRR对RAS和AVP的上游控制表示。我们的研究表明 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