Dept. of Physiology, Hypertension and Renal Center of Excellence, Tulane Univ. Health Sciences Center, New Orleans, LA 70112, USA.
Am J Physiol Renal Physiol. 2013 Oct 1;305(7):F1031-41. doi: 10.1152/ajprenal.00024.2013. Epub 2013 Aug 7.
In the present study, we examine the hypothesis that the nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a protective role in the development of ANG II-induced hypertension and renal injury by minimizing oxidative stress and the inflammation induced by TNF-α. Systolic blood pressure (SBP) and renal injury responses to chronic infusions of ANG II (via implanted minipumps) were evaluated for 2 wk in wild-type (WT) and in eNOS knockout mice (KO) cotreated with or without a superoxide (O2(-)) scavenger, tempol (400 mg/l in the drinking water), or a TNF-α receptor blocker, etanercept (5 mg/kg/day ip). In study 1, when ANG II was given at a dose of 25 ng/min, it increased mean SBP in WT mice (Δ36 ± 3 mmHg; n = 7), and this effect was attenuated in mice pretreated with tempol (Δ24 ± 3 mmHg; n = 6). In KO mice (n = 9), this dose of ANG II resulted in severe renal injury associated with high mortality. To avoid this high mortality in KO, study 2 was conducted with a lower dose of ANG II (10 ng/min) that increased SBP slightly in WT (Δ17 ± 7 mmHg; n = 6) but exaggeratedly in KO (Δ48 ± 12 mmHg, n = 6) associated with severe renal injury. Cotreatment with either tempol (n = 6) or etanercept (n = 6) ameliorated the hypertensive, as well as the renal injury responses in KO compared with WT. These data demonstrate a protective role for eNOS activity in preventing renal inflammatory injury and hypertension induced by chronic increases in ANG II.
在本研究中，我们检验了这样一个假设，即内皮型一氧化氮合酶（eNOS）产生的一氧化氮（NO）通过最小化氧化应激和肿瘤坏死因子-α（TNF-α）诱导的炎症，在血管紧张素 II（ANG II）诱导的高血压和肾脏损伤的发展中发挥保护作用。通过植入的微量渗透泵，用 ANG II（以 25ng/min 的剂量）对野生型（WT）和 eNOS 敲除（KO）小鼠进行慢性输注，评估其 2 周的收缩压（SBP）和肾脏损伤反应，同时这些小鼠分别接受超氧化物（O2(-)）清除剂替米沙坦（400mg/l 饮用水）或 TNF-α 受体阻滞剂依那西普（5mg/kg/day ip）的联合治疗。在研究 1 中，当给予 ANG II 剂量为 25ng/min 时，它会使 WT 小鼠的平均 SBP 升高（Δ36±3mmHg；n=7），而预先用替米沙坦治疗的小鼠（Δ24±3mmHg；n=6）的这种作用会减弱。在 KO 小鼠（n=9）中，这种剂量的 ANG II 会导致严重的肾脏损伤和高死亡率。为了避免 KO 小鼠的这种高死亡率，研究 2 采用了 ANG II 的较低剂量（10ng/min），该剂量仅使 WT 小鼠的 SBP 略有升高（Δ17±7mmHg；n=6），但 KO 小鼠的 SBP 显著升高（Δ48±12mmHg，n=6），同时伴有严重的肾脏损伤。与 WT 相比，替米沙坦（n=6）或依那西普（n=6）的联合治疗均能改善 KO 小鼠的高血压和肾脏损伤反应。这些数据表明，eNOS 活性在预防慢性 ANG II 增加引起的肾脏炎症性损伤和高血压方面发挥了保护作用。
