中文摘要
间隙连接在肾脏的病理生理过程中具有重要作用,其可以调节氧化应激减轻肾脏氧化损伤,但机理并未完全明确。硫氧还蛋白结合蛋白(TXNIP)-硫氧还蛋白(Trx)是重要的氧化还原调控蛋白,被称为氧化还原体,参与了肾脏病的发生发展。甘草次酸是甘草的主要单体之一,是常用的间隙连接抑制剂,可抑制间隙连接蛋白及信号通讯。本研究将通过体外肾脏细胞、体内转基因小鼠细胞氧化损伤模型明确甘草次酸通过调节间隙连接调控TXNIP-Trx氧化还原体的机理,阐明间隙连接对氧化还原体蛋白、功能、活性的调节机制,并通过检测慢性肾脏病不同肾功能患者血、尿Trx水平及氧化还原状态,明确其在慢性肾脏病中的意义。本研究将进一步完善甘草解毒“阻邪入里”的中医理论,并为肾脏病的治疗提供新的治疗靶点和药物。
英文摘要
Gap junction (GJ) plays a pivotal role on renal physiological and pathophysiological process. GJ can regulate oxidative stress and protect renal against oxidative injury. However the detailed mechanisms and roles in kidney are still unclear. Among the 21 connexins, connexin 43 (Cx43) is one of the most widely expressed and intensively studied connexins. Thioredoxin interacting protein (TXNIP) and thioredoxin (Trx) are important redox regulators and have been called redoxisome since they are attracting growing attentions in a variety of biologic process. Given that glycyrrhetinic acid(GA), the main extract from glycyrrhizae herb, is one of the usually used gap junction blockers and can decrease connexins and suppress GJ-mediated communication. What is the relationship between GJ and TXNIP-Trx redoxisome? In this study we will investigate whether and how GJ regulate TXNIP-Trx redoxisome in kidney..Normal rat kidney tubular cell lines and murine podocytes oxidative injury model in vitro and Cx43 transgenic mice model in vivo are involved in this study to elucidate the mechanisms underling the regulation of GA on TXNIP-Trx redoxisome mediated by GJ. These effects may be multiple, involving the regulation on protein, function and activity of TXNIP-Trx redoxisome. Furthermore, patients with different stage of chronic kidney disease are enrolled in this investigation. The urinary and serum Trx protein level, reduced form and oxidized form of Trx will be analyzed to clarify the role of Trx in chronic kidney disease. .In general, our study will complete the traditional Chinese medicine theory that glycyrrhizae protects kidney from toxicity by block the diffusion of pathogenic factors. Moreover, our research will provide the novel therapeutic target and strategy in the treatment of kidney disease.
