Onozato Maristela Lika, Tojo Akihiro, Kobayashi Naohiko, Goto Atsuo, Matsuoka Hiroaki, Fujita Toshiro
Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Nephrol Dial Transplant. 2007 May;22(5):1314-22. doi: 10.1093/ndt/gfl780. Epub 2007 Feb 26.
Angiotensin II blockade and spironolactone effectively reduces proteinuria in humans. To clarify the mechanisms of the beneficial effect of blockade of both aldosterone and angiotensin II, we associated the aldosterone antagonist eplerenone to an angiotensin-converting enzyme inhibitor (ACEI) and examined the effect on renal transforming growth factor (TGF)-beta expression and oxidative stress by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the Dahl salt-sensitive rat with heart failure (DSHF).
Dahl salt-resistant control rats and DSHF rats were fed with 8% NaCl diet and at 11 weeks the DSHF rats were treated with vehicle, eplerenone (Epl), trandolapril or a combination of both drugs for 7 weeks.
DSHF rats showed increased NADPH oxidase and decreased superoxide dismutase (SOD) resulting in increased oxidative stress. ACEI and Epl reduced NADPH oxidase showing an additive effect in their combination; ACEI increased manganese SOD (MnSOD) and Epl increased MnSOD, copper-zinc SOD and catalase, resulting in the lowest levels of oxidative stress with the combination therapy. Glomerulosclerosis and proteinuria were increased in the DSHF rats, and Epl suppressed them more effectively than ACEI to levels not different from the combination of both, showing a positive correlation with NADPH oxidase expression and TGF-beta. Renal TGF-beta was specifically suppressed with Epl
The association of Epl to ACEI is beneficial due to further reduction of NADPH oxidase and specific inhibition of TGF-beta resulting in improvement of renal damage.
血管紧张素II阻断和螺内酯可有效降低人类蛋白尿。为阐明醛固酮和血管紧张素II阻断的有益作用机制，我们将醛固酮拮抗剂依普利酮与血管紧张素转换酶抑制剂（ACEI）联合使用，并在患有心力衰竭的Dahl盐敏感大鼠（DSHF）中研究其对肾转化生长因子（TGF）-β表达及烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶介导的氧化应激的影响。
给Dahl盐抵抗对照大鼠和DSHF大鼠喂食8%NaCl饮食，11周时对DSHF大鼠用赋形剂、依普利酮（Epl）、trandolapril或两种药物联合治疗7周。
DSHF大鼠NADPH氧化酶增加，超氧化物歧化酶（SOD）减少，导致氧化应激增加。ACEI和Epl可降低NADPH氧化酶，二者联合有相加作用；ACEI增加锰超氧化物歧化酶（MnSOD），Epl增加MnSOD、铜锌超氧化物歧化酶和过氧化氢酶，联合治疗使氧化应激水平降至最低。DSHF大鼠肾小球硬化和蛋白尿增加，Epl比ACEI更有效地抑制它们，使其水平与两者联合治疗时无差异，且与NADPH氧化酶表达和TGF-β呈正相关。Epl可特异性抑制肾TGF-β。
Epl与ACEI联合有益，因为可进一步降低NADPH氧化酶并特异性抑制TGF-β，从而改善肾损伤。
