Suehiro Takaichi, Tsuruya Kazuhiko, Ikeda Hirofumi, Toyonaga Jiro, Yamada Shunsuke, Noguchi Hideko, Tokumoto Masanori, Kitazono Takanari
Department of Medicine and Clinical Science (T.S., K.T., H.I., J.T., S.Y., H.N., T.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease (K.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Internal Medicine (S.Y., M.T.), Fukuoka Dental College, Fukuoka 814-0175, Japan.
Endocrinology. 2015 Jul;156(7):2657-66. doi: 10.1210/en.2014-1369. Epub 2015 Apr 14.
Chronic inhibition of nitric oxide synthase by N(ω)-nitro-L-arginine methyl ester (L-NAME) causes progressive renal injury and systemic hypertension. Angiotensin II (Ang II) has been conventionally regarded as one of the primary causes of renal injury. We reported previously that such renal injury was almost completely suppressed by both an Ang II type I receptor blocker and an aldosterone antagonist. The aldosterone antagonist also inhibited the systemic Ang II elevation. Therefore, it remains to be elucidated whether Ang II or aldosterone directly affects the development of such renal injury. In the present study, we investigated the role of aldosterone in the pathogenesis of renal injury induced by L-NAME-mediated chronic nitric oxide synthase inhibition in male Wistar rats (aged 10 wk). Serial analyses demonstrated that the renal injury and inflammation in L-NAME-treated rats was associated with elevation of both Ang II and aldosterone. To investigate the direct effect of aldosterone on the renal injury, we conducted adrenalectomy (ADX) and aldosterone supplementation in L-NAME-treated rats. In ADX rats, aldosterone was undetectable, and renal injury and inflammation were almost completely prevented by ADX, although systemic and local Ang II and blood pressure were still elevated. Aldosterone supplementation reversed the beneficial effect of ADX. The present study indicates that aldosterone rather than Ang II plays a central and direct role in the pathogenesis of renal injury by L-NAME through inflammation, independent of its systemic hemodynamic effects.
N（ω）-硝基-L-精氨酸甲酯（L-NAME）对一氧化氮合酶的慢性抑制会导致进行性肾损伤和全身性高血压。血管紧张素II（Ang II）一直被传统地认为是肾损伤的主要原因之一。我们之前报道过，这种肾损伤几乎完全被I型Ang II受体阻滞剂和醛固酮拮抗剂所抑制。醛固酮拮抗剂也抑制了全身性Ang II的升高。因此，Ang II或醛固酮是否直接影响这种肾损伤的发展仍有待阐明。在本研究中，我们研究了醛固酮在雄性Wistar大鼠（10周龄）中由L-NAME介导的慢性一氧化氮合酶抑制所诱导的肾损伤发病机制中的作用。系列分析表明，L-NAME处理的大鼠中的肾损伤和炎症与Ang II和醛固酮的升高有关。为了研究醛固酮对肾损伤的直接影响，我们对L-NAME处理的大鼠进行了肾上腺切除术（ADX）和醛固酮补充。在ADX大鼠中，醛固酮无法检测到，尽管全身性和局部性Ang II以及血压仍然升高，但ADX几乎完全预防了肾损伤和炎症。醛固酮补充逆转了ADX的有益作用。本研究表明，醛固酮而非Ang II在L-NAME所致肾损伤的发病机制中通过炎症发挥核心和直接作用，而与其全身性血流动力学效应无关。
