The role of soluble prorenin receptor in hypertension associated with obesity

项目摘要/摘要 肥胖症的流行，目前影响着美国超过36.5%的人口 在美国，这导致了高血压患病率的上升。我们最近发现， 肥胖刺激可溶性形式的前肾素受体(PRR)sPRR分泌到 血浆。在检测组织中sPRR蛋白浓度时，我们发现 高脂对照组小鼠肝脏、脂肪组织和肾脏中sPRR蛋白水平的变化 饮食与喂食低脂肪饮食的小鼠相比。新的初步数据显示，注入一种 重组小鼠sPRR在喂饲标准饲料的小鼠体内激活局部和循环RAS 增加肾皮质血管紧张素原(AGT)和循环肾素水平。与一致 这些结果，我们的新结果表明，在脂肪PRR KO中血浆sPRR升高 小鼠肾脏皮质血管紧张素II水平升高。尿液 这些小鼠体内的加压素水平也显著增加。加上我们之前的工作，这些 结果提示sPRR对肾素血管紧张素系统(RAS)和机体的调节作用 液体体积。为了验证这一想法，3T3-L1细胞和人类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细胞中的表达及人培养液中AGT的分泌 HepG2。此外，与我们的sPRR中和抗体孵育可降低AngII水平。 在3T3-L1细胞的培养液中。由于sPRR在小鼠体内的输注增加了血浆肾素水平，我们 同时观察sPRR对肾脏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 通过一种机制刺激sPRR的产生导致高血压 激活RAS，增加AVP。我们将检验组织衍生sPRR的假设 介导血管紧张素II诱导的高血压与肥胖相关，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 将证明肥胖是否通过一条以前未知的途径来调节 以sPRR对RAS和AVP的上游控制为代表。我们的研究指出了一种独特的 SPRR在肥胖相关高血压中的功能作用。

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.