NKA/Src信号复合体氧化应激放大作用发生机制及在肾间质纤维化中的作用研究

氧化应激是肾间质纤维化的重要致病因素。NOXs系统活化是肾脏活性氧簇（ROS）产成的主要来源。我们既往研究证实：钠钾ATP酶（NKA）/Src信号复合体可被外源性ROS激活；抑制NOXs活化可部分逆转UUO鼠肾小管NKA表达的下调及Src的活化；抑制NOXs活化或抑制Src活化均可显著减轻UUO肾间质纤维化。基于NKA/Src信号复合体活化本身又可使细胞内ROS生成增加的文献背景，本课题拟通过细胞实验，观察NOXs系统活化与NKA/Src信号复合体这种氧化应激放大作用之间的关系及调控机制；并通过给予UUO模型不同干预，在在体水平观察NKA/Src信号复合体氧化应激放大作用在肾间质纤维化中的病理生理作用。研究结果有助于从氧化应激调控角度阐明NKA/Src信号复合体在慢性肾间质纤维化进展中的作用。

Oxidative stress is an important cause of renal interstitial fibrosis, with the NADPH oxidase (NOXs) as the major contributor to the generation of reactive oxygen species (ROS). The Na/K-ATPase (NKA)/Src receptor complex is the key receptor complex among NKA-related receptor complexes, with NKA acts as an important regulator of Src activation and subsequent signal transduction. In our previous study, we found that exogenous ROS could induce the activation of the NKA/Src complex with subsequent activation of Src/ERK pathway in LLCPK1 cells. We also found that inhibition of NOXs activation and subsequent ROS production could partly reversed the decreased expression of NKA and increased activation of Src in UUO animals. Furthermore, inhibition of NOXs or Src activation could alleviate renal interstitial fibrosis in UUO. Interestingly, it was reported that activation of the NKA/Src complex per ce could induce intracellular ROS production in previous studies. Based on these data, we hypothesized that NKA/Src complex might contribute to the renal fibrosis via its oxidative stress amplification effect in the present project. We will explore the potential role of NOXs in the generation of oxidative stress amplification effect of NKA/Src complex in in vitro studies. The contribution of the oxidative stress amplification effect to the development of interstitial fibrosis will be further explored in UUO animals. We hope the results would help to elucidate the role of NKA/Src complex in the development of renal interstitial fibrosis from the point of view of oxidative stress regulation.