Intrarenal ghrelin receptor inhibition ameliorates angiotensin II-dependent hypertension in rats.
Intrarenal ghrelin receptor inhibition ameliorates angiotensin II-dependent hypertension in rats.
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肾内生长素释放肽受体抑制可改善大鼠血管紧张素 II 依赖性高血压。
DOI：
10.1152/ajprenal.00010.2018
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Padia,ShetalH
中科院分区：
文献类型：
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作者：
Kemp,BrandonA;Howell,NancyL;Padia,ShetalH
肾内生长激素释放肽受体（GR）定位于集合管（CD）细胞，在啮齿动物中，其增加上皮Na+通道（αENaC）依赖性钠重吸收。我们假设肾内GR siRNA慢性GR抑制通过减少α ENaC依赖性钠重吸收降低血管紧张素II依赖性高血压患者的血压（BP）。单侧肾切除的Sprague-Dawley大鼠（n= 121）接受皮下渗透泵，用于长期全身递送血管紧张素II或溶媒（5%葡萄糖水溶液）。大鼠还接受载体、GR siRNA或乱序（SCR）siRNA的肾内输注。在接受肾内载体或肾内SCR siRNA的大鼠中，全身性血管紧张素II输注增加了第1天的钠潴留和BP，并且BP在整个5天研究中保持升高。这些大鼠在输注5天后也表现出CD GR表达增加。然而，肾内GR siRNA输注可在第1天阻止血管紧张素II介导的钠潴留，与单独使用血管紧张素II相比，可诱导持续负累积钠平衡，并长期降低血压。肾小球滤过率和肾血流量在GR siRNA输注大鼠中保持不变。全身性血管紧张素II输注也增加了肾内SCR siRNA大鼠的血清醛固酮水平、CD αENaC和磷酸化血清和糖皮质激素诱导激酶1表达;然而，尽管暴露于相同的全身性血管紧张素II，但在存在肾内GR siRNA的情况下未观察到这些效应。这些数据表明，长期抑制肾内GR活性可显著降低α ENaC依赖性钠潴留，导致负累积钠平衡，从而改善大鼠血管紧张素II诱导的高血压。肾脏GR代表了治疗高血压和其他钠潴留状态的新治疗靶点。
The intrarenal ghrelin receptor (GR) is localized to collecting duct (CD) cells, where it increases epithelial Na+channel (αENaC)-dependent sodium reabsorption in rodents. We hypothesized that chronic GR inhibition with intrarenal GR siRNA lowers blood pressure (BP) in angiotensin II-dependent hypertension via reductions in αENaC-dependent sodium reabsorption. Uninephrectomized Sprague-Dawley rats (n= 121) received subcutaneous osmotic pumps for chronic systemic delivery of angiotensin II or vehicle (5% dextrose in water). Rats also received intrarenal infusion of vehicle, GR siRNA, or scrambled (SCR) siRNA. In rats receiving intrarenal vehicle or intrarenal SCR siRNA, systemic angiotensin II infusion increased sodium retention and BP onday 1, and BP remained elevated throughout the 5-day study. These rats also demonstrated increased CD GR expression after 5 days of infusion. However, intrarenal GR siRNA infusion prevented angiotensin II-mediated sodium retention onday 1, induced a continuously negative cumulative sodium balance compared with angiotensin II alone, and reduced BP chronically. Glomerular filtration rate and renal blood flow remained unchanged in GR siRNA-infused rats. Systemic angiotensin II infusion also increased serum aldosterone levels, CD αENaC, and phosphorylated serum and glucocorticoid-inducible kinase 1 expression in rats with intrarenal SCR siRNA; however, these effects were not observed in the presence of intrarenal GR siRNA, despite exposure to the same systemic angiotensin II. These data demonstrate that chronic inhibition of intrarenal GR activity significantly reduces αENaC-dependent sodium retention, resulting in a negative cumulative sodium balance, thereby ameliorating angiotensin II–induced hypertension in rats. Renal GRs represent a novel therapeutic target for the treatment of hypertension and other sodium-retaining states.