Asahi K, Ichimori K, Nakazawa H, Izuhara Y, Inagi R, Watanabe T, Miyata T, Kurokawa K
Institute of Medical Sciences and Department of Internal Medicine, and Department of Physiology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Kidney Int. 2000 Oct;58(4):1780-7. doi: 10.1111/j.1523-1755.2000.00340.x.
Advanced glycation end products (AGEs) are elevated in renal failure and have been implicated in the pathogenesis of several uremic complications. Their formation is closely associated with oxidative stress. The recent observation that nitric oxide (NO) has an antioxidant effect led us to examine the possible role of NO in the generation of AGEs.
We examined the effect of NO donors, 2, 2'-(hydroxynitrosohydrazono)bis-ethanamine (NOC18) and S-nitroso-N-acetyl-DL-penicillamine (SNAP), on the in vitro formation of pentosidine, which was used as a surrogate marker for AGEs. Bovine serum albumin was incubated under air at 37 degrees C in a medium containing either several AGE precursors or uremic plasma. To elucidate further the mechanism of the NO effect on AGE formation, we examined the generation of free radicals and carbonyls in pentose-driven pentosidine formation.
NO donors significantly inhibit the formation of pentosidine in a dose-dependent manner. The effect is abolished by the addition of a NO scavenging agent, 2-(4-carboxyphenyl)-4,4,5, 5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO). The inhibitory effect results from NO but not from the NO donor molecule. It is best explained by the ability of NO to scavenge carbon-centered radicals, hydroxyl radical, and carbonyl compounds.
NO inhibits pentosidine formation by scavenging free radicals and by inhibiting carbonyl compound formation. NO might be implicated in the atherogenic and inflammatory effects of AGEs: Reduced NO production and increased oxidative stress associated with atherosclerotic lesions may accelerate AGE formation and, thus, exacerbate endothelial dysfunction and accelerate the development of atherosclerosis in uremia.
晚期糖基化终末产物（AGEs）在肾衰竭时升高，并与多种尿毒症并发症的发病机制有关。其形成与氧化应激密切相关。最近观察到一氧化氮（NO）具有抗氧化作用，这促使我们研究NO在AGEs生成中的可能作用。
我们研究了NO供体2,2'-（羟基亚硝基肼基）双乙胺（NOC18）和S-亚硝基-N-乙酰-DL-青霉胺（SNAP）对体外生成戊糖苷的影响，戊糖苷用作AGEs的替代标志物。牛血清白蛋白在含有几种AGE前体或尿毒症血浆的培养基中于37℃空气下孵育。为了进一步阐明NO对AGE形成的作用机制，我们研究了戊糖驱动的戊糖苷形成过程中自由基和羰基的生成。
NO供体以剂量依赖性方式显著抑制戊糖苷的形成。加入NO清除剂2-（4-羧基苯基）-4,4,5,5-四甲基咪唑啉-1-氧基3-氧化物（羧基-PTIO）可消除该作用。抑制作用源于NO而非NO供体分子。这最好用NO清除碳中心自由基、羟基自由基和羰基化合物的能力来解释。
NO通过清除自由基和抑制羰基化合物形成来抑制戊糖苷的形成。NO可能与AGEs的动脉粥样硬化和炎症作用有关：与动脉粥样硬化病变相关的NO生成减少和氧化应激增加可能加速AGE形成，从而加剧内皮功能障碍并加速尿毒症患者动脉粥样硬化的发展。
