Yoshida Shigetaka, Ishizawa Kenichi, Ayuzawa Nobuhiro, Ueda Kohei, Takeuchi Maki, Kawarazaki Wakako, Fujita Toshiro, Nagase Miki
Department of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan,
Clin Exp Nephrol. 2014 Aug;18(4):593-9. doi: 10.1007/s10157-013-0893-6. Epub 2013 Oct 24.
The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS-activated hypertensive patients.
Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect.
High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment.
Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients.
肾素-血管紧张素-醛固酮系统（RAAS）在慢性肾脏病（CKD）进展的发病机制中起关键作用。阿利吉仑是一种直接肾素抑制剂，可抑制RAAS的限速步骤，且无任何替代途径。已证实它可降低接受血管紧张素阻断治疗的CKD患者的蛋白尿。然而，很少有报告评估阿利吉仑作为一线药物在RAAS激活的高血压患者中对抗CKD进展的优势。
筑波高血压小鼠（THM）是携带人肾素和人血管紧张素原基因的双转基因小鼠，给予高盐饮食，并分别用肼屈嗪、雷米普利和阿利吉仑治疗10周。在实验期间每2周测量一次血压和尿白蛋白排泄量。我们评估了肾脏组织学变化和基因表达。测量血浆血管紧张素浓度以评估RAAS抑制作用。
高盐负荷的THM表现出严重高血压和肾损伤。所有抗高血压药物均能降低血压并预防肾脏疾病进展。尽管降压效果相当，但RAAS阻断剂显示出比肼屈嗪更高的肾脏保护作用。阿利吉仑表现出比雷米普利更强的肾脏保护作用。喂食正常盐和高盐的THM血浆血管紧张素浓度均升高。肼屈嗪未改变血浆血管紧张素浓度。雷米普利显著降低血管紧张素II浓度。阿利吉仑治疗几乎完全抑制了血管紧张素I，并导致血管紧张素II浓度低于雷米普利治疗组。
在RAAS激活的病理状态下，阿利吉仑通过抑制血管紧张素I和II来预防肾脏疾病进展。我们的数据表明肾素抑制剂可用于预防CKD患者的肾脏疾病进展。
