Fulvene-5 inhibition of Nadph oxidases attenuates activation of epithelial sodium channels in A6 distal nephron cells.
Fulvene-5 inhibition of Nadph oxidases attenuates activation of epithelial sodium channels in A6 distal nephron cells.
复制标题
Fulvene-5 抑制 Nadph 氧化酶会减弱 A6 远端肾单位细胞上皮钠通道的激活。
DOI：
10.1152/ajprenal.00098.2013
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Helms,MyN
中科院分区：
文献类型：
--
作者：
Trac,David;Liu,Bingchen;Pao,AlanC;Thomas,SheelaV;Park,Michael;Downs,CharlesA;Ma,He-Ping;Helms,MyN
Nadph氧化酶4是肾脏中活性氧（ROS）生成的重要细胞来源。新的抗氧化药物，如Nox4抑制剂化合物，正在开发中。然而，很少有实验证据表明Nadph氧化酶在肾脏中的生物学作用和调节。本研究表明，Fulvene-5是Nox生成ROS的有效抑制剂，并报道了Nox异构体在A6远端肾细胞中通过氧化信号传导和细胞拉伸激活上皮钠通道（ENaC）的作用。使用单通道膜片钳分析，我们报告了Fulvene-5阻断了A6细胞在h2o2处理下通常观察到的ENaC活性的增加：在Fulvene-5处理后，ENaC活性的平均值从基线水平1.04±0.18 （mean±SE）下降到0.25±0.08。在Fulvene-5存在的情况下，h2o2处理不能提高ENaC的活性。此外，Fulvene-5处理A6细胞阻断了A6细胞的渗透细胞拉伸反应，表明nox来源的ROS的拉伸激活在ENaC调节中起着重要作用。总之，这些发现表明，Fulvene-5，也许还有其他种类的抗氧化抑制剂，可能代表了一类新的化合物，可用于治疗由不适当的离子通道活性引起的病理性疾病，如高血压。
Nadph oxidase 4 is an important cellular source of reactive oxygen species (ROS) generation in the kidney. Novel antioxidant drugs, such as Nox4 inhibitor compounds, are being developed. There is, however, very little experimental evidence for the biological role and regulation of Nadph oxidase isoforms in the kidney. Herein, we show that Fulvene-5 is an effective inhibitor of Nox-generated ROS and report the role of Nox isoforms in activating epithelial sodium channels (ENaC) in A6 distal nephron cells via oxidant signaling and cell stretch activation. Using single-channel patch-clamp analysis, we report that Fulvene-5 blocked the increase in ENaC activity that is typically observed with H2O2treatment of A6 cells: average ENaCNPovalues decreased from a baseline level of 1.04 ± 0.18 (means ± SE) to 0.25 ± 0.08 following Fulvene-5 treatment. H2O2treatment failed to increase ENaC activity in the presence of Fulvene-5. Moreover, Fulvene-5 treatment of A6 cells blocked the osmotic cell stretch response of A6 cells, indicating that stretch activation of Nox-derived ROS plays an important role in ENaC regulation. Together, these findings indicate that Fulvene-5, and perhaps other classes of antioxidant inhibitors, may represent a novel class of compounds useful for the treatment of pathological disorders stemming from inappropriate ion channel activity, such as hypertension.