Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Nephron Exp Nephrol. 2009;113(2):e66-76. doi: 10.1159/000228714. Epub 2009 Jul 16.
Adenosine monophosphate activated protein kinase (AMPK) has a protective effect on lipid peroxidation. Adiponectin and AMPK might have a role in the pathogenesis of diabetic nephropathy. Blockade of the renin-angiotensin system (RAS) increases adiponectin levels and reduces oxidative stress. The objective of the present study was to examine lipid peroxidation via adiponectin and AMPK activation in the kidneys of KK-A(y)/Ta mice by RAS inhibitors, such as enalapril and/or losartan.
KK-A(y)/Ta mice were given enalapril (2.5 mg/kg/day) and/or losartan (25 mg/kg/day), or hydralazine (25 mg/kg/day) in the drinking water for 8 weeks starting at 8 weeks of age. They were divided into 5 groups as follows: enalapril 2.5 mg/kg/day treatment group (n = 5), losartan 25 mg/kg/day treatment group (n = 5), enalapril 2.5 mg/kg/day + losartan 25 mg/kg/day combination treatment group (n = 5), hydralazine 25 mg/kg/day treatment group (n = 5) and tap water group as the untreated group (n = 5). The urinary albumin/creatinine ratio (ACR), serum adiponectin and systemic blood pressure were measured as test parameters. Expressions of adiponectin, phospho-AMPKalpha (p-AMPKalpha) and phospho-acetyl CoA carboxylase(beta) (p-ACC(beta)) in the kidneys were evaluated by Western blot analyses. Pathological changes of glomeruli were evaluated by light microscopy. Accumulations of N(epsilon)-(carboxymethyl) lysine (CML), malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE) in glomeruli were evaluated by immunohistochemical analyses.
Enalapril and/or losartan improved levels of urinary ACR with activation of adiponectin, p-AMPKalpha and p-ACC(beta) in the kidneys. CML, MDA and 4-HNE expressions in glomeruli were significantly suppressed by enalapril and/or losartan, especially in the combination treatment group.
It appears that enalapril and/or losartan, especially in combination, inhibited accumulation of CML/MDA/4-HNE in diabetic renal tissues. These effects might be related to lipid peroxidation via tissue-specific activation of adiponectin and AMPK.
一磷酸腺苷激活的蛋白激酶 (AMPK) 对脂质过氧化具有保护作用。脂联素和 AMPK 可能在糖尿病肾病的发病机制中起作用。肾素-血管紧张素系统 (RAS) 的阻断会增加脂联素水平并减少氧化应激。本研究的目的是通过 RAS 抑制剂，如依那普利和/或氯沙坦，检测 KK-A(y)/Ta 小鼠肾脏中的脂质过氧化通过脂联素和 AMPK 的激活。
8 周龄时，KK-A(y)/Ta 小鼠开始在饮用水中给予依那普利（2.5 mg/kg/天）和/或氯沙坦（25 mg/kg/天），或肼屈嗪（25 mg/kg/天），连续 8 周。它们被分为以下 5 组：依那普利 2.5 mg/kg/天治疗组（n = 5）、氯沙坦 25 mg/kg/天治疗组（n = 5）、依那普利 2.5 mg/kg/天+氯沙坦 25 mg/kg/天联合治疗组（n = 5）、肼屈嗪 25 mg/kg/天治疗组（n = 5）和自来水组作为未处理组（n = 5）。尿白蛋白/肌酐比 (ACR)、血清脂联素和全身血压作为检测参数进行测量。通过 Western blot 分析评估肾脏中脂联素、磷酸化 AMPKalpha(p-AMPKalpha)和磷酸化乙酰辅酶 A 羧化酶(beta)(p-ACC(beta))的表达。通过光镜评估肾小球的病理变化。通过免疫组化分析评估肾小球中 N(epsilon)-(羧甲基)赖氨酸 (CML)、丙二醛 (MDA)和 4-羟基-2-壬烯醛 (4-HNE)的积累。
依那普利和/或氯沙坦通过激活肾脏中的脂联素、p-AMPKalpha 和 p-ACC(beta)，改善了尿 ACR 的水平。依那普利和/或氯沙坦可显著抑制肾小球中 CML、MDA 和 4-HNE 的表达，尤其是联合治疗组。
依那普利和/或氯沙坦，尤其是联合使用，可抑制糖尿病肾组织中 CML/MDA/4-HNE 的积累。这些作用可能与通过组织特异性激活脂联素和 AMPK 导致的脂质过氧化有关。
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