Mervaala Eero, Finckenberg Piet, Lapatto Risto, Müller Dominik N, Park Joon-Keun, Dechend Ralf, Ganten Detlev, Vapaatalo Heikki, Luft Friedrich C
Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, University of Helsinki, Finland.
Kidney Int. 2003 Aug;64(2):501-8. doi: 10.1046/j.1523-1755.2003.00108.x.
Angiotensin II (Ang II)-induced renal injury is associated with perivascular inflammation, cell proliferation, and increased superoxide production in the vascular wall. We tested whether lipoic acid, an endogenous antioxidant, protects against the Ang II-induced inflammatory response and end-organ damage.
Light microscopy, immunohistochemistry, electrophoretic mobility shift assay, Northern blots, and high-pressure liquid chromatography (HPLC) were used in kidneys from double transgenic rats (dTGR) harboring human renin and angiotensinogen genes and normotensive Sprague Dawley (SD) rats. The effects of lipoic acid supplementation for three weeks were examined in dTGR and SD rats.
Lipoic acid effectively prevented Ang II-induced glomerular and vascular damage in the kidneys and completely prevented the development of albuminuria. Ang II-induced leukocyte infiltration and cell proliferation in the kidney were attenuated. The redox-sensitive transcription factors nuclear factor (kappa) B (NF-kappa B) and activator protein-1 (AP-1) in the kidneys were increased in dTGR compared with SD, and were effectively reduced. Renal glutathione levels were much higher in dTGR than in SD, while the opposite was true for cysteine levels. These results suggested increased renal glutathione oxidation in dTGR, leading to cysteine shortage. Lipoic acid partly prevented renal cysteine depletion and increased hepatic cysteine and glutathione concentrations. This effect was accompanied by increased hepatic gamma-glutamylcysteine synthetase mRNA expression.
Our in vivo results suggest that lipoic acid protects against Ang II-induced renal injury through anti-inflammatory/antioxidative mechanisms. The effects are associated with decreased NF-kappa B and AP-1 activation, as well as improved thiol homeostasis.
血管紧张素II（Ang II）诱导的肾损伤与血管周围炎症、细胞增殖以及血管壁中超氧化物生成增加有关。我们测试了内源性抗氧化剂硫辛酸是否能预防Ang II诱导的炎症反应和终末器官损伤。
对携带人肾素和血管紧张素原基因的双转基因大鼠（dTGR）以及正常血压的斯普拉格-道利（SD）大鼠的肾脏进行光学显微镜检查、免疫组织化学、电泳迁移率变动分析、Northern印迹和高压液相色谱（HPLC）分析。研究了硫辛酸补充三周对dTGR和SD大鼠的影响。
硫辛酸有效预防了Ang II诱导的肾脏肾小球和血管损伤，并完全预防了蛋白尿的发生。Ang II诱导的肾脏白细胞浸润和细胞增殖得到减轻。与SD大鼠相比，dTGR大鼠肾脏中对氧化还原敏感的转录因子核因子κB（NF-κB）和激活蛋白-1（AP-1）增加，而硫辛酸有效降低了它们的水平。dTGR大鼠肾脏中的谷胱甘肽水平远高于SD大鼠，而半胱氨酸水平则相反。这些结果表明dTGR大鼠肾脏中谷胱甘肽氧化增加，导致半胱氨酸短缺。硫辛酸部分预防了肾脏半胱氨酸耗竭，并增加了肝脏半胱氨酸和谷胱甘肽浓度。这种作用伴随着肝脏γ-谷氨酰半胱氨酸合成酶mRNA表达的增加。
我们的体内研究结果表明，硫辛酸通过抗炎/抗氧化机制预防Ang II诱导的肾损伤。其作用与NF-κB和AP-1激活的降低以及硫醇稳态的改善有关。
