Ishikawa Yayoi, Nishikimi Toshio, Akimoto Kazumi, Ishimura Kimihiko, Ono Hidehiko, Matsuoka Hiroaki
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
Hypertension. 2006 Jun;47(6):1075-83. doi: 10.1161/01.HYP.0000221605.94532.71. Epub 2006 Apr 24.
We have shown recently that fasudil, a Rho-kinase inhibitor, has renoprotective effects in salt-sensitive hypertensive rats. We hypothesized that activation of Rho-kinase is involved in the pathogenesis of glomerulosclerosis in malignant hypertensive rats. To test this hypothesis, we studied the following 4 groups: control Wistar-Kyoto rats, untreated deoxycorticosterone-acetate salt spontaneously hypertensive rats (DOCA-SHR), low-dose fasudil-treated DOCA-SHR, and high-dose fasudil-treated DOCA-SHR. After 3 weeks of treatment, the effects of fasudil were examined. DOCA-SHR was characterized by increased blood pressure (BP); increased kidney weight; decreased renal function; increased proteinuria; abnormal histological findings; increased monocyte/macrophage infiltration; increased urinary 8-isoprostran levels; increased gene expression of collagen I, collagen III, transforming growth factor-beta, and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits (p40phox, p47phox, and p67phox); and decreased gene expression of endothelial NO synthase (eNOS) in the renal cortex as compared with Wistar-Kyoto rats. Long-term high-dose fasudil treatment significantly improved renal function and histological findings without changing BP, as compared with untreated DOCA-SHR. Interestingly, long-term fasudil treatment significantly decreased monocyte/macrophage infiltration and urinary 8-isoprostran excretion, in association with decreased mRNA levels of transforming growth factor-beta, collagen I, collagen III, and NADPH oxidase subunits (p40phox, p47phox, and p67phox), and increased mRNA levels of eNOS in the renal cortex. Long-term low-dose fasudil treatment tended to improve these variables slightly but did not affect most of them significantly. Our results suggest that long-term fasudil treatment provides renoprotective effects independent of BP-lowering activity. These renoprotective effects are associated with inhibition of extracellular matrix gene expression, monocyte/macrophage infiltration, oxidative stress, and upregulation of eNOS gene expression.
我们最近发现，Rho激酶抑制剂法舒地尔对盐敏感性高血压大鼠具有肾脏保护作用。我们推测，Rho激酶的激活参与了恶性高血压大鼠肾小球硬化的发病机制。为了验证这一假设，我们研究了以下4组：对照Wistar-Kyoto大鼠、未治疗的醋酸脱氧皮质酮盐自发性高血压大鼠（DOCA-SHR）、低剂量法舒地尔治疗的DOCA-SHR和高剂量法舒地尔治疗的DOCA-SHR。治疗3周后，检测法舒地尔的效果。DOCA-SHR的特征为血压（BP）升高；肾脏重量增加；肾功能下降；蛋白尿增加；组织学检查结果异常；单核细胞/巨噬细胞浸润增加；尿8-异前列腺素水平升高；I型胶原、III型胶原、转化生长因子-β和还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶亚基（p40phox、p47phox和p67phox）的基因表达增加；与Wistar-Kyoto大鼠相比，肾皮质中内皮型一氧化氮合酶（eNOS）的基因表达下降。与未治疗的DOCA-SHR相比，长期高剂量法舒地尔治疗可显著改善肾功能和组织学检查结果，而血压不变。有趣的是，长期法舒地尔治疗可显著减少单核细胞/巨噬细胞浸润和尿8-异前列腺素排泄，同时肾皮质中转化生长因子-β、I型胶原、III型胶原和NADPH氧化酶亚基（p40phox、p47phox和p67phox）的mRNA水平下降，eNOS的mRNA水平升高。长期低剂量法舒地尔治疗倾向于轻微改善这些变量，但对大多数变量没有显著影响。我们的结果表明，长期法舒地尔治疗可提供独立于降压活性的肾脏保护作用。这些肾脏保护作用与细胞外基质基因表达的抑制、单核细胞/巨噬细胞浸润、氧化应激以及eNOS基因表达的上调有关。
