Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANG II-induced hypertensive mice
Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANG II-induced hypertensive mice
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DOI：
10.1152/ajprenal.00152.2017
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发表时间：
2017-12-01
影响因子：
4.2
通讯作者：
Gonzalez, Alexis A.
中科院分区：
文献类型：
--
作者：
Prieto, Minolfa C.;Reverte, Virginia;Gonzalez, Alexis A.
肾小管内血管紧张素（ANG）II增加是通过激活上皮钠通道（ENaC）和其他转运体促进远端钠重吸收的关键决定因素，这会导致高血压的发生。在血管紧张素II诱导的高血压中，集合管（CD）中肾素原受体（PRR）表达增加，这与钠转运体的刺激以及由此导致的高血压有关。沿肾单位的PRR缺失对血压调节和钠处理的影响仍存在争议。在本研究中，我们利用集合管特异性缺失PRR的小鼠模型（CDPRR - KO）来研究PRR在肾功能调节和血压中的作用。在基础条件下，CDPRR - KO小鼠肾功能下降，收缩压降低，同时伴有较高的钠排泄分数和较低的尿液血管紧张素II水平。在血管紧张素II输注14天（400 ng·kg⁻¹·min⁻¹）后，CDPRR - KO小鼠收缩压和舒张压的升高幅度减小。与野生型小鼠相比，CDPRR - KO小鼠尿液中裂解的α - ENaC和γ - ENaC含量较低，血管紧张素II和肾素含量也较低。在从CDPRR - KO小鼠分离的集合管中，膜片钳研究表明，由于活性通道减少和开放概率降低，血管紧张素II依赖性的ENaC活性刺激减弱。这些数据表明，在慢性血管紧张素II输注过程中，集合管PRR通过增强肾素活性、增加血管紧张素II以及激活远端肾单位节段的ENaC，对肾功能和血压反应起作用。
Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Na+ reabsorption via activation of epithelial Na+ channels (ENaC) and other transporters, which leads to the development of high blood pressure (BP). In ANG II-induced hypertension, there is increased expression of the prorenin receptor (PRR) in the collecting duct (CD), which has been implicated in the stimulation of the sodium transporters and resultant hypertension. The impact of PRR deletion along the nephron on BP regulation and Na+ handling remains controversial. In the present study, we investigate the role of PRR in the regulation of renal function and BP by using a mouse model with specific deletion of PRR in the CD (CDPRR-KO). At basal conditions, CDPRR-KO mice had decreased renal function and lower systolic BP associated with higher fractional Na+ excretion and lower ANG II levels in urine. After 14 days of ANG II infusion (400 ng.kg(-1).min(-1)), the increases in systolic BP and diastolic BP were mitigated in CDPRR-KO mice. CDPRR-KO mice had lower abundance of cleaved alpha ENaC and gamma ENaC, as well as lower ANG II and renin content in urine compared with wild-type mice. In isolated CD from CDPRR-KO mice, patch-clamp studies demonstrated that ANG II-dependent stimulation of ENaC activity was reduced because of fewer active channels and lower open probability. These data indicate that CD PRR contributes to renal function and BP responses during chronic ANG II infusion by enhancing renin activity, increasing ANG II, and activating ENaC in the distal nephron segments.