内质网应激在醛固酮诱导肾小管上皮细胞凋亡中作用及其机制研究

Renal interstitial fibrosis has become a common way and the main pathological basis of chronic kidney disease progression to end-stage renal. The previous studies of our group have showed that aldosterone induced glomerular fibrosis partly via NHE1. But at present the mechanism of aldosterone induced renal tubular epithelial cell apoptosis has not been clarified. Studies have shown that the endoplasmic reticulum stress and nerve cell apoptosis injury are closely related, many factors are involved in endoplasmic reticulum stress, in which ROS can not only induce endoplasmic reticulum stress, but also mediate apoptosis, and it plays an important role in a variety of kidney disease pathogenesis. In view of the endoplasmic reticulum stress and the pathogenesis of oxidative stress involved in aldosterone induced renal injury, our study plan to observe whether aldosterone can induce oxidative stress and endoplasmic reticulum stress and their relationship to each other in vitro and in vivo, and demonstrate the application of antioxidants on endoplasmic reticulum stress and renal injury. We hope that we can this study can show that aldosterone can induce the generation of reactive oxygen species, further activate endoplasmic reticulum stress induced apoptosis pathway, thus provide a new theoretical basis and target in chronic kidney disease therapy and prevention.

肾间质纤维化已经成为各种慢性肾脏病进展到终末期肾病的共同途径和主要病理学基础。本课题组的前期研究初步证明了醛固酮所致的肾小球纤维化系通过介导NHE1表达和活性增加所致，但目前醛固酮诱导肾小管上皮细胞凋亡的具体机制并未阐明清楚。有研究发现内质网应激与神经细胞的凋亡损伤密切相关，多种因素均能够引起内质网应激，其中活性氧作为信号分子，不仅能够诱导内质网应激，其也能够介导凋亡的发生，并且在多种肾脏疾病的发病机制中起着重要作用。鉴于内质网应激在肾脏损伤发病机制中的作用和氧化应激参与了醛固酮诱导的肾损伤模型，本研究拟分别从细胞水平和动物水平观察醛固酮能否诱导氧化应激和内质网应激及其相互关系，并探讨应用抗氧化剂对内质网应激和肾损伤是否具有缓解作用。我们希望通过本研究能够证实：醛固酮能够诱导活性氧的生成进并一步激活内质网应激诱导的凋亡通路，为慢性肾脏病的研究和防治提供新的理论依据和靶点。

肾间质纤维化已经成为各种慢性肾脏病进展到终末期肾病的共同途径和主要病理学基础。但目前醛固酮诱导肾小管上皮细胞凋亡的具体机制并未阐明清楚。鉴于内质网应激在肾脏损伤发病机制中的作用和氧化应激参与了醛固酮诱导的肾损伤模型，本课题分别从细胞水平和动物水平观察醛固酮能否诱导氧化应激和内质网应激，并探讨了应用抗氧化剂或将 CHOP 基因干扰之后对醛固酮诱导肾小管细胞凋亡的影响。我们通过本研究已经初步证实：醛固酮能够诱导活性氧的生成，进一步激活内质网应激诱导的凋亡通路；线粒体ROS介导的NLRP3炎症小体在醛固酮诱导的上皮细胞凋亡中有着重要作用；内质网应激在尿毒症心肌损伤中有重要作用及，TUDCA可缓解尿毒症大鼠内质网应激导致的心肌细胞凋亡。本项目研究结果为慢性肾脏病的研究和防治提供新的理论依据和靶点。