Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Am J Hypertens. 2010 May;23(5):575-80. doi: 10.1038/ajh.2009.273. Epub 2010 Jan 14.
A direct renin inhibitor (DRI) had a benefit in decreasing albuminuria in type 2 diabetic patients having already been treated with angiotensin (Ang) II type 1 receptor blocker (ARB), suggesting that aliskiren may have another effect other than blockade of the traditional renin-angiotensin system (RAS). Recently, prorenin bound to (pro)renin receptor ((P)RR) was found and shown to evoke two pathways; the generation of Ang peptides and the receptor-dependent activation of extracellular signal-related protein kinase (ERK). Because (P)RR is present in the podocytes, a central component of the glomerular filtration barrier, we hypothesized that aliskiren influences the (P)RR-induced two pathways in human podocytes.
Human podocytes were treated with 2 nmol/l prorenin in the presence and absence of an angiotensin-converting enzyme inhibitor (ACEi) imidaprilat, an ARB candesartan, a DRI aliskiren, or the siRNA knocking down the (P)RR mRNA and the intracellular AngII levels and the phosphorylation of ERK were determined.
The expression of (P)RR mRNA of human podocytes was unaffected by the treatment with RAS inhibitors, but decreased by 69% with the siRNA treatment. The basal levels of intracellular AngII and the prorenin-induced increase in intracellular AngII were significantly reduced by aliskiren and siRNA treatment, compared with imidaprilat and candesartan. The prorenin-induced ERK activation was reduced to control level by the siRNA treatment, but it was unaffected by imidaprilat, candesartan, or aliskiren.
Aliskiren is the most potent inhibitor of intracellular AngII levels of human podocytes among RAS inhibitors, although it is incapable of inhibiting the (P)RR-dependent ERK phosphorylation.
在已经接受血管紧张素（Ang）II 型 1 型受体阻滞剂（ARB）治疗的 2 型糖尿病患者中，直接肾素抑制剂（DRI）可降低蛋白尿，这表明阿利西嗪可能具有除阻断传统肾素-血管紧张素系统（RAS）以外的其他作用。最近，发现并证实前肾素与（pro）肾素受体（（P）RR）结合，并引发两条途径；血管紧张素肽的产生和细胞外信号相关蛋白激酶（ERK）的受体依赖性激活。由于（P）RR 存在于足细胞中，即肾小球滤过屏障的核心成分，我们假设阿利西嗪会影响人足细胞中（P）RR 诱导的两条途径。
在存在和不存在血管紧张素转换酶抑制剂（ACEi）依那普利、ARB 坎地沙坦、DRI 阿利西嗪或敲低（P）RR mRNA 的 siRNA 的情况下，用 2 nmol/l 前肾素处理人足细胞，并测定细胞内 AngII 水平和 ERK 的磷酸化。
人足细胞（P）RR mRNA 的表达不受 RAS 抑制剂治疗的影响，但 siRNA 治疗可使其降低 69%。与依那普利和坎地沙坦相比，阿利西嗪和 siRNA 处理可显著降低基础细胞内 AngII 水平和前肾素诱导的细胞内 AngII 增加。siRNA 处理可将前肾素诱导的 ERK 激活降低至对照水平，但对依那普利、坎地沙坦或阿利西嗪无影响。
在 RAS 抑制剂中，阿利西嗪是降低人足细胞细胞内 AngII 水平的最有效抑制剂，尽管它不能抑制（P）RR 依赖性 ERK 磷酸化。
