Losartan prevents the elevation of blood pressure in adipose-PRR deficient female mice while elevated circulating sPRR activates the renin-angiotensin system
Losartan prevents the elevation of blood pressure in adipose-PRR deficient female mice while elevated circulating sPRR activates the renin-angiotensin system
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DOI：
10.1152/ajpheart.00473.2018
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发表时间：
2019-03-01
影响因子：
4.8
通讯作者：
Yiannikouris, Frederique
中科院分区：
文献类型：
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作者：
Gatineau, Eva;Cohn, Dianne M.;Yiannikouris, Frederique
脂肪组织中的前肾素受体（PRR）缺失会升高高脂（HF）饮食雄性小鼠的收缩压（SBP）和循环可溶性PRR（sPRR）。然而，在血压控制的关键器官中，脂肪PRR和sPRR对肾素-血管紧张素系统（RAS）调节作用的性别差异尚不明确。因此，我们评估了脂肪PRR敲除（KO）雌性小鼠的血压以及全身和肾内RAS状态。在HF饮食喂养的脂肪-PRR KO小鼠中，氯沙坦阻断RAS可减缓SBP升高。喂食HF饲料的脂肪PRR KO雌性小鼠的肾皮质中ANG II水平显着增加，但全身性并未增加。与野生型（WT）小鼠相比，HF饮食喂养的脂肪-PRR KO小鼠表现出更高的血管加压素水平、水潴留和更低的尿量。结果还表明，脂肪PRR的缺失增加了循环sPRR和总肝脏sPRR含量，表明肝脏是脂肪PRR KO小鼠血浆sPRR升高的主要来源。为了模拟循环sPRR的升高并确定全身sPRR对RAS和加压素调节的直接贡献，用重组sPRR输注饲喂标准饮食的C57 BL/6雌性小鼠。sPRR输注增加血浆肾素水平、肾和肝血管紧张素原表达和血管加压素。一起这些结果表明，脂肪-PRR的缺失诱导SBP的升高，可能是由肾内ANGII依赖性机制介导的，并且sPRR通过其激活RAS和增加血管加压素水平的能力参与RAS调节和体液稳态。前肾素受体敲除雌性小鼠。另外。我们的数据支持可溶性前肾素受体在肾素-血管紧张素系统激活和加压素调节中的作用。
Deletion of the prorenin receptor (PRR) in adipose tissue elevates systolic blood pressure (SBP) and the circulating soluble form of PRR (sPRR) in male mice fed a high-fat (HF) diet. However, sex differences in the contribution of adipose-PRR and sPRR to the regulation of the renin-angiotensin system (RAS) in key organs for blood pressure control are undefined. Therefore, we assessed blood pressure and the systemic and intrarenal RAS status in adipose-PRR knockout (KO) female mice. Blockade of RAS with losartan blunted SBP elevation in HF diet-fed adipose-PRR KO mice. ANG II levels were significantly increased in the renal cortex of HF diet-fed adipose-PRR KO female mice, but not systemically. HF diet-fed adipose-PRR KO mice exhibited higher vasopressin levels, water retention, and lower urine output than wild-type (WT) mice. The results also showed that deletion of adipose-PRR increased circulating sPRR and total hepatic sPRR contents, suggesting the liver as a major source of elevated plasma sPRR in adipose-PRR KO mice. To mimic the elevation of circulating sPRR and define the direct contribution of systemic sPRR to the regulation of the RAS and vasopressin, C57BL/6 female mice fed a standard diet were infused with recombinant sPRR. sPRR infusion increased plasma renin levels, renal and hepatic angiotensinogen expression, and vasopressin. Together. these results demonstrate that the deletion of adipose-PRR induced an elevation of SBP likely mediated by an intrarenal ANG II-dependent mechanism and that sPRR participates in RAS regulation and body fluid homeostasis via its capacity to activate the RAS and increase vasopressin levels.NEW & NOTEWORTHY The elevation of systolic blood pressure appears to be primarily mediated by cortical ANG II in high-fat diet-fed adipose-prorenin receptor knockout female mice. In addition. our data support a role for soluble prorenin receptor in renin-angiotensin system activation and vasopressin regulation.