Inhibition of mineralocorticoid receptor is a renoprotective effect of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin.
Inhibition of mineralocorticoid receptor is a renoprotective effect of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin.
复制标题
DOI：
10.1097/hjh.0b013e328341cedf
复制
发表时间：
2011-03
影响因子：
4.9
通讯作者：
Murohara T
中科院分区：
文献类型：
--
作者：
Cheng XW;Kuzuya M;Sasaki T;Inoue A;Hu L;Song H;Huang Z;Li P;Takeshita K;Hirashiki A;Sato K;Shi GP;Okumura K;Murohara T
矿皮质激素受体与慢性心肾疾病的发病机制有关。他汀类药物改善蛋白尿肾病患者肾脏重塑和功能障碍。我们的目的是阐明他汀类药物在肾功能不全中的有益作用和作用机制。在12 ~ 20周龄饲喂高盐饮食的达尔盐敏感大鼠，分别给予载药、还原性烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶抑制剂罗布麻碱、合成组织蛋白酶抑制剂E64d或低剂量或高剂量匹伐他汀（1或3 mg/kg每日）。喂食低盐饮食的老鼠作为对照。高盐饮食的大鼠出现大量蛋白尿和肾小球硬化；两种剂量的匹伐他汀均可减弱这些变化。药物处理大鼠衰竭肾脏中矿化皮质激素受体、血管紧张素转换酶、血管紧张素II型1受体（AT1R）、单核细胞趋化蛋白-1、骨桥蛋白、巨噬细胞浸润和NADPH亚基（gp91phox、p22phox和Rac1）的mrna或蛋白含量显著高于对照大鼠肾脏。两种剂量的匹伐他汀都能显著减弱这些变化。匹伐他汀的这些作用被罗布麻素和E64d所模拟。皮伐他汀和罗布麻碱预处理可抑制血管紧张素诱导的足细胞矿化皮质激素受体mRNA和蛋白表达。匹伐他汀的有益作用可能至少部分归因于，在盐诱导的高血压Dahl盐敏感大鼠模型中，at1r介导的NADPH氧化酶激活诱导的盐皮质激素受体依赖性炎症介质、基质蛋白和组织蛋白酶表达的衰减。
The mineralocorticoid receptor has been implicated in the pathogenesis of chronic cardiorenal disease. Statins improve renal remodeling and dysfunction in patients with proteinuric kidney diseases. We aimed to clarify the beneficial effects and mechanisms of action of statins in renal insufficiency. Dahl salt-sensitive rats fed a high-salt diet were treated from 12 to 20 weeks of age with vehicle, the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin, the synthetic cathepsin inhibitor E64d, or a low or high dosage of pitavastatin (1 or 3 mg/kg daily). Rats fed a low-salt diet served as controls. Rats on the high-salt diet developed massive proteinuria and glomerulosclerosis; these changes were attenuated by both doses of pitavastatin. The amounts of mRNAs or proteins for mineralocorticoid receptor, angiotensin-converting enzyme, angiotensin II type 1 receptor (AT1R), monocyte chemoattractant protein-1, osteopontin, macrophage infiltration, and NADPH subunits (gp91phox, p22phox, and Rac1) were significantly higher in the failing kidneys of vehicle-treated rats than in the kidneys of control rats. Either dose of pitavastatin significantly attenuated these changes. These effects of pitavastatin were mimicked by those of apocynin and E64d. Pretreatment with pitavastatin and apocynin inhibited mRNA and protein of mineralocorticoid receptor induced by angiotensin II in cultured podocytes. The beneficial effects of pitavastatin are likely attributable, at least in part, to attenuation of the mineralocorticoid receptor-dependent inflammatory mediator, matrix protein, and cathepsin expressions induced by AT1R-mediated NADPH oxidase activation in the kidneys of a salt-induced hypertensive Dahl salt-sensitive rat model.