Regulatory interactions between inducible nitric oxide synthase and eicosanoids in glomerular immune injury.
Regulatory interactions between inducible nitric oxide synthase and eicosanoids in glomerular immune injury.
复制标题
诱导型一氧化氮合酶和类二十烷酸在肾小球免疫损伤中的调节相互作用。
DOI：
10.1046/j.1523-1755.1998.00791.x
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发表时间：
1998
影响因子：
19.6
通讯作者：
Sharma,M
中科院分区：
文献类型：
--
作者：
Lianos,EA;Guglielmi,K;Sharma,M
诱导型一氧化氮合酶和类二十烷酸在肾小球免疫损伤中的调节相互作用。在抗肾小球基底膜抗体诱导的大鼠肾小球免疫损伤模型中，类似于人快速进展性肾小球肾炎，我们探讨了诱导型一氧化氮合酶（iNOS）的激活是否调节类二十烷酸的合成 源自花生四烯酸的环氧化或脂氧化。在损伤早期（24小时），使用选择性抑制剂L-N6-（1-亚氨基乙基）赖氨酸（L-NIL）抑制iNOS，剂量足以减少尿中硝酸盐/亚硝酸盐的排泄，减少前列腺素PGE2和PGI2的肾小球合成，但对血栓素A2（TxA2）没有影响。 5-羟基二十碳四烯酸(HETE)、15-HETE和白三烯B4(LTB4)的合成也减少。 12-HETE 保持不变。我们还探讨了花生四烯酸环氧化和脂氧化类二十烷酸对 iNOS 表达的影响。给予环氧合酶（COX）抑制剂吲哚美辛，其剂量足以抑制肾小球前列腺素合成，增加肾小球中 iNOS mRNA 水平。给予足以抑制肾小球LTB4合成的剂量的5-脂氧合酶(5-LO)抑制剂MK-0591也增加了iNOS mRNA。 5-LO抑制对iNOS表达的影响比COX抑制更明显。在给予 iNOS 抑制剂、L-NIL 或吲哚美辛的肾病动物中，蛋白尿恶化。在服用 5-脂氧合酶抑制剂的患者中，尿蛋白排泄量没有变化。这些观察结果表明了肾小球肾炎中花生四烯酸和 L-精氨酸：NO 通路之间的调节相互作用。这些相互作用对于考虑基于抑制 iNOS 或特定类二十烷酸的抗炎策略非常重要。
Regulatory interactions between inducible nitric oxide synthase and eicosanoids in glomerular immune injury.In a rat model of glomerular immune injury induced by administration of anti-glomerular basement membrane antibody and resembling human rapidly progressive glomerulonephritis, we explored whether activation of inducible nitric oxide synthase (iNOS) regulates synthesis of eicosanoids originating from cyclooxygenation or lipoxygenation of arachidonic acid. At early stages (24 hr) of injury, inhibition of iNOS using the selective inhibitor L-N6-(1-iminoethyl) lysine (L-NIL) at doses sufficient to reduce urinary excretion of nitrate/nitrite, reduced glomerular synthesis of the prostaglandins PGE2and PGI2, but had no effect on that of thromboxane A2(TxA2). The syntheses of 5-hydroxyeicosatetraenoic acid (HETE), 15-HETE and leukotriene B4(LTB4) were also reduced. That of 12-HETE remained unchanged. We also explored the effect of arachidonate cyclooxygenation and lipoxygenation eicosanoids on iNOS expression. Administration of the cyclooxygenase (COX) inhibitor, indomethacin, at doses sufficient to inhibit glomerular prostaglandin synthesis, increased iNOS mRNA levels in glomeruli. Administration of the 5-lipoxygenase (5-LO) inhibitor, MK-0591, at doses sufficient to inhibit glomerular LTB4synthesis also increased iNOS mRNA. The effect of 5-LO inhibition on iNOS expression was more pronounced than that of COX inhibition. In nephritic animals given the iNOS inhibitor, L-NIL, or indomethacin proteinuria worsened. In those given the 5-lipoxygenase inhibitor there was no change in urine protein excretion. These observations point to regulatory interactions between the arachidonic acid and the L-arginine:NO pathways in glomerulonephritis. These interactions are of importance in considering antiinflammatory strategies based on inhibition of iNOS or of specific eicosanoids.