Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
Eur J Pharmacol. 2013 Jan 15;699(1-3):233-40. doi: 10.1016/j.ejphar.2012.11.034. Epub 2012 Nov 28.
Nitric oxide (NO) deficiency contributes to hypertension and end-organ damage. Three nitric oxide synthase (NOS) isoforms have been identified: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). Whether selective nNOS or iNOS inhibition exacerbates kidney damage in spontaneously hypertensive rats (SHRs) remains unclear. Seven-week-old SHRs were randomly assigned to 4 groups (n=8 for each group): group 1, SHRs receiving no treatment; group 2 (SHR+7-NI), SHRs given 7-nitroindazole (7-NI, nNOS inhibitor) in their drinking water (10mg/kg/day); group 3 (SHR+salt), SHRs given 1% NaCl; and group 4 (SHR+AG), SHRs given 0.1% aminoguanidine (AG; iNOS inhibitor) in drinking water. The mean arterial pressure of SHRs treated with salt was significantly elevated compared with untreated controls. While AG caused a decrease of mean arterial pressure at 8 and 12 weeks of age in SHRs, both 7-NI and salt exacerbated kidney injury. In addition, AG significantly increased l-arginine levels and the l-arginine-to-asymmetric dimethylarginine (ADMA) ratio in the kidney. Salt treatment decreased renal nNOS-α protein levels and reduced dimethylarginine dimethylaminohydrolase (DDAH) activity. Salt and AG treatment increased nNOS-β and l-citrulline levels in SHR kidneys. AG attenuates hypertension development by upregulation of l-citrulline-to- l-arginine conversion and an increase in the l-arginine-to-ADMA ratio in SHR kidneys. 7-NI impairs renal function but has no effect on blood pressure, suggesting reno-protective role for the nNOS. Salt exacerbates kidney damage mainly through decreasing renal nNOS-α protein levels and DDAH activity. Our findings highlight the protective role of the nNOS/NO pathway in the development of kidney damage in SHRs.
一氧化氮（NO）缺乏可导致高血压和靶器官损害。目前已鉴定出 3 种一氧化氮合酶（NOS）同工型：神经元型 NOS（nNOS）、诱导型 NOS（iNOS）和内皮型 NOS（eNOS）。选择性抑制 nNOS 或 iNOS 是否会加重自发性高血压大鼠（SHR）的肾脏损害尚不清楚。本研究将 7 周龄 SHR 随机分为 4 组（每组 8 只）：第 1 组，未治疗的 SHR；第 2 组（SHR+7-NI），给予 SHR 饮用水中 7-硝基吲唑（7-NI，nNOS 抑制剂）（10mg/kg/天）；第 3 组（SHR+盐），给予 SHR 1%NaCl；第 4 组（SHR+AG），给予 SHR 饮用水中 0.1%氨基胍（AG；iNOS 抑制剂）。与未治疗的对照组相比，给予盐的 SHR 的平均动脉压明显升高。虽然 AG 在 SHR 8 周和 12 周时降低了平均动脉压，但 7-NI 和盐均加重了肾脏损伤。此外，AG 显著增加了 SHR 肾脏中的 l-精氨酸水平和 l-精氨酸/非对称二甲基精氨酸（ADMA）比值。盐处理降低了肾脏 nNOS-α 蛋白水平并降低了二甲基精氨酸二甲胺水解酶（DDAH）活性。盐和 AG 处理增加了 SHR 肾脏中的 nNOS-β 和 l-瓜氨酸水平。AG 通过上调 l-瓜氨酸向 l-精氨酸的转化和增加 l-精氨酸/ADMA 比值来减轻 SHR 肾脏中的高血压发展。7-NI 损害肾功能但对血压无影响，提示 nNOS 具有肾保护作用。盐主要通过降低肾脏 nNOS-α 蛋白水平和 DDAH 活性来加重肾脏损伤。我们的研究结果强调了 nNOS/NO 途径在 SHR 肾脏损伤发展中的保护作用。
