Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport.
Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport.
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DOI：
10.1152/ajprenal.00088.2016
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
N. Ramkumar;D. Stuart;Elena V. Mironova;V. Bugay;Shuping Wang;N. Abraham;A. Ichihara;J. Stockand;D. Kohan
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文献类型：
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作者：
N. Ramkumar;D. Stuart;Elena V. Mironova;V. Bugay;Shuping Wang;N. Abraham;A. Ichihara;J. Stockand;D. Kohan
由于与整体或肾特异性PRR敲除（KO）相关的发育异常，肾小管前肾素受体（PRR）的生理意义一直难以阐明。我们最近开发了一种使用Pax 8/LC 1转基因的诱导性肾小管全PRR KO，并证明了1月龄时肾小管PRR的破坏不会导致肾脏组织学异常。在此，我们研究了肾小管PRR在血压（BP）调节和Na（+）排泄中的作用，并研究了PRR调节Na（+）平衡的信号机制。在对照组和喂食正常或低Na（+）饮食的PRR KO小鼠之间未观察到血压的可检测差异。然而，与对照组相比，PRR KO小鼠在正常和低Na（+）摄入下血浆肾素浓度升高，累积Na（+）平衡降低。PRR KO小鼠在血管紧张素II（ANG II）输注后的高血压反应减弱，Na（+）潴留减少。此外，PRR KO小鼠具有显著较低的上皮Na（+）通道（ENaC-α）表达。用小鼠前肾素处理增加了分离的开放集合管（CD）中的ENaC活性，而PRR拮抗作用降低。蛋白激酶A和Akt的抑制阻止了原肾素的作用，但不受AT 1，ERK 1/2或p38 MAPK通路阻断的影响。总之，这些数据表明肾小管PRR可能通过PKA/Akt依赖性途径的直接原肾素/肾素刺激刺激CD ENaC活性。肾小管PRR的缺失促进Na（+）消耗并降低对ANG II的高血压反应。
The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.