Febuxostat ameliorates high salt intake-induced hypertension and renal damage in Dahl salt-sensitive rats
Febuxostat ameliorates high salt intake-induced hypertension and renal damage in Dahl salt-sensitive rats
复制标题
DOI：
10.1097/hjh.0000000000003012
复制
发表时间：
2022-02-01
影响因子：
4.9
通讯作者：
Ito, Osamu
中科院分区：
文献类型：
--
作者：
Miura, Takahiro;Sakuyama, Akihiro;Ito, Osamu
目的：一些临床研究报道，黄嘌呤氧化还原酶抑制剂具有抗高血压和肾脏保护作用，但其机制尚未完全确定。本研究旨在通过检测非布司他（一种新型选择性黄嘌呤氧化还原酶抑制剂）在Dahl盐敏感大鼠中的作用来阐明这些机制。方法：8周龄雄性Dahl盐敏感大鼠，分别给予正常盐（0.6%NaCl）和高盐（8%NaCl）饮食8周。一部分喂食高盐饲料的大鼠同时接受非布司他（3 mg/kg/天）治疗。此外，在高盐饮食喂养4或8周后检查了非布司他（3 mg/kg/天）的急性效应。结果如下：非布司他治疗8周可减轻高盐饮食诱导的高血压、肾功能不全、肾小球损伤和肾间质纤维化。非布司他治疗降低了H2 O2和丙二醛的尿排泄以及肾硫代巴比妥酸反应物质含量。高盐饮食增加黄嘌呤氧化还原酶的活性和表达在近端小管和髓质髓质。非布司他完全抑制黄嘌呤氧化还原酶活性，并减弱高盐饮食增加的黄嘌呤氧化还原酶表达。高盐饮食喂养4或8周后，非布司他一过性增加尿量和Na+排泄，而血压或尿肌酐排泄无变化。结论：在Dahl盐敏感大鼠中，非布司他改善高盐饮食诱导的高血压和肾损伤，并降低肾氧化应激。非布司他的降压作用可能部分通过利尿和利钠作用介导。
Objective: Several clinical studies have reported that xanthine oxidoreductase inhibitors have antihypertensive and renal protective effects but their mechanisms have not been fully determined. This study aims to clarify these mechanisms by examining the effects of febuxostat, which is a novel selective xanthine oxidoreductase inhibitor, in Dahl salt-sensitive rats. Methods: Eight-week-old male Dahl salt-sensitive rats were fed a normal salt (0.6% NaCl) or high salt (8% NaCl) diet for 8 weeks. A portion of the rats that were fed high salt diet were treated with febuxostat (3 mg/kg per day) simultaneously. Additionally, acute effects of febuxostat (3 mg/kg per day) were examined after high salt diet feeding for 4 or 8 weeks. Results: Treatment with febuxostat for 8 weeks attenuated high salt diet-induced hypertension, renal dysfunction, glomerular injury, and renal interstitial fibrosis. Febuxostat treatment reduced urinary excretion of H2O2 and malondialdehyde and renal thiobarbituric acid reactive substances content. High salt diet increased xanthine oxidoreductase activity and expression in the proximal tubules and medullary interstitium. Febuxostat completely inhibited xanthine oxidoreductase activity and attenuated the high salt diet-increased xanthine oxidoreductase expression. Febuxostat transiently increased urine volume and Na+ excretion without change in blood pressure or urinary creatinine excretion after high salt diet feeding for 4 or 8 weeks. Conclusion: Febuxostat ameliorates high salt diet-induced hypertension and renal damage with a reduction of renal oxidative stress in Dahl salt-sensitive rats. The antihypertensive effect of febuxostat may be mediated in part by diuretic and natriuretic action.