Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Dept. of Neurobiology, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
Dept. of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Dept. of Anesthesiology, Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, Weifang Medical University, Weifang, China.
Redox Biol. 2021 Feb;39:101836. doi: 10.1016/j.redox.2020.101836. Epub 2020 Dec 17.
Renal ischemia-reperfusion (IR) injury is a common cause of acute kidney injury (AKI), which is associated with oxidative stress and reduced nitric oxide (NO) bioactivity and increased risk of developing chronic kidney disease (CKD) and cardiovascular disease (CVD). New strategies that restore redox balance may have therapeutic implications during AKI and associated complications.
To investigate the therapeutic value of boosting the nitrate-nitrite-NO pathway during development of IR-induced renal and cardiovascular dysfunction.
Male C57BL/6 J mice were given sodium nitrate (10 mg/kg, i. p) or vehicle 2 h prior to warm ischemia of the left kidney (45 min) followed by sodium nitrate supplementation in the drinking water (1 mmol/kg/day) for the following 2 weeks. Blood pressure and glomerular filtration rate were measured and blood and kidneys were collected and used for biochemical and histological analyses as well as renal vessel reactivity studies. Glomerular endothelial cells exposed to hypoxia-reoxygenation, with or without angiotensin II, were used for mechanistic studies.
IR was associated with reduced renal function and slightly elevated blood pressure, in combination with renal injuries, inflammation, endothelial dysfunction, increased Ang II levels and Ang II-mediated vasoreactivity, which were all ameliorated by nitrate. Moreover, treatment with nitrate (in vivo) and nitrite (in vitro) restored NO bioactivity and reduced mitochondrial oxidative stress and injuries.
Acute treatment with inorganic nitrate prior to renal ischemia may serve as a novel therapeutic approach to prevent AKI and CKD and associated risk of developing cardiovascular dysfunction.
肾缺血再灌注（IR）损伤是急性肾损伤（AKI）的常见原因，与氧化应激、一氧化氮（NO）生物活性降低以及发生慢性肾脏病（CKD）和心血管疾病（CVD）的风险增加有关。恢复氧化还原平衡的新策略在 AKI 及其相关并发症期间可能具有治疗意义。
研究在 IR 诱导的肾和心血管功能障碍发展过程中增强硝酸盐-亚硝酸盐-NO 途径的治疗价值。
雄性 C57BL/6J 小鼠在左肾热缺血（45 分钟）前 2 小时给予硝酸钠（10mg/kg，腹腔注射）或载体，随后在饮用水中补充硝酸钠（1mmol/kg/天）持续 2 周。测量血压和肾小球滤过率，并收集血液和肾脏用于生化和组织学分析以及肾血管反应性研究。将肾小球内皮细胞暴露于缺氧-复氧中，有或没有血管紧张素 II，用于进行机制研究。
IR 与肾功能降低和血压略有升高有关，同时伴有肾损伤、炎症、内皮功能障碍、Ang II 水平升高和 Ang II 介导的血管反应性增加，这些都被硝酸盐改善。此外，用硝酸盐（体内）和亚硝酸盐（体外）处理可恢复 NO 生物活性，并减少线粒体氧化应激和损伤。
在肾缺血前进行急性无机硝酸盐治疗可能是预防 AKI 和 CKD 及其相关心血管功能障碍风险的一种新的治疗方法。
