Nuclear factor-κB inhibitors as potential novel anti-inflammatory agents for the treatment of immune glomerulonephritis
Nuclear factor-κB inhibitors as potential novel anti-inflammatory agents for the treatment of immune glomerulonephritis
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DOI：
10.1016/s0002-9440(10)64425-2
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发表时间：
2002-10-01
影响因子：
6
通讯作者：
Gómez-Guerrero, C
中科院分区：
文献类型：
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作者：
López-Franco, O;Suzuki, Y;Gómez-Guerrero, C
核因子-kappaB调节与炎症反应有关的几个基因，是一个有趣的治疗靶点。我们研究了在体外具有抗炎活性的胶质毒素(一种真菌代谢产物)和Parthenolide(一种植物提取物)对实验性肾小球肾炎进展的影响。在抗Thy 1.1大鼠模型中，胶质毒素(75 mg/只/只/d，10天，n=18)可显著减少蛋白尿、肾小球病变和单核细胞浸润。在小鼠抗肾小球系膜细胞肾炎中，小白菊内酯(70 mg/只/天，7天，17只小鼠)可显著减少蛋白尿、血尿和肾小球增殖。定位于肾小球和肾小管上皮细胞的核因子-kappaB活性可被胶质毒素或巴豆内酯减弱，并伴随着肾脏单核细胞趋化蛋白-1和诱导型一氧化氮合酶表达的减少。在培养的肾小球系膜细胞和单核细胞中，胶质细胞毒素和Parthenolide通过阻断IkappaBalpha亚单位的磷酸化/降解来抑制由脂多糖和细胞因子诱导的NF-kappaB的激活和炎症基因的表达。综上所述，胶质毒素和Parthenolide通过抑制核因子-kappaB的激活和调节基因的表达来预防蛋白尿和肾脏损害。这可能是治疗免疫性和炎症性肾脏疾病的一种新方法。
Nuclear factor (NF)-kappaB regulates several genes implicated in the inflammatory response and represents an interesting therapeutic target. We examined the effects of gliotoxin (a fungal metabolite) and parthenolide (a plant extract), which possess anti-inflammatory activities in vitro, on the progression of experimental glomerulonephritis. in the anti-Thy 1.1 rat model, gliotoxin (75 mug/rat/day, 10 days, n = 18 rats) markedly reduced proteinuria, glomerular lesions, and monocyte infiltration. In anti-mesangial cell nephritis in mice, parthenolide (70 mug/mouse/day, 7 days, n = 17 mice) significantly decreased proteinuria, hematuria, and glomerular proliferation. NF-kappaB activity, localized in glomerular and tubular cells, was attenuated by either gliotoxin or parthenolide, in association with diminished renal expression of monocyte chemoattractant protein-1 and inducible nitric oxide synthase. in cultured mesangial cells and monocytes, gliotoxin and parthenolide inhibited NF-kappaB activation and expression of inflammatory genes induced by lipopolysaccharide and cytokines; by blocking the phosphorylation/degradation of the IkappaBalpha subunit. In summary, gliotoxin and parthenolide prevent proteinuria and renal lesions by inhibiting NF-kappaB activation and expression of regulated genes. This may represent a novel approach for the treatment of immune and inflammatory renal diseases.