黄芪通过抑制mTORC1信号通路，活化自噬，延缓糖尿病肾病进展的研究

Diabetic nephropathy (DN) is the most devastating complications of diabetes and the leading single cause of end-stage kidney disease. The therapies on DN may be effective in slowing progression but ineffective in reversing established complications. Emerging body of evidence suggested that the pathogenesis of DN is associated with impaired autophagic via the activating of mTORC1. Hence, targeting the autophagic and mTORC1 signaling is an intriguing therapeutic strategy for DN. In the previous study, we have confirmed that astragalus membranaceus alleviating proteinuria in DN is associated with improving endoplasmic reticulum (ER) stress. Based on the direct link between ER stress and autophagy, we rise the hypothesis that astragalus membranaceus inhibit the progression of diabetic nephropathy is association with the inhibition of mTORC1 and activation of autophagy. To validate the hypothesis, we adopt DN rat induced with STZ, and podocytes induced to ER stress or autophagy impaired to observe the effects of astragalus membranaceus，astragaloside IV and astragalin on the progress of glomerulosclerosis, activity of mTORC1 and autophagy. The results of this study may offer new mechanism of astragalus membranaceus on renoprotection in DN, provides a theoretical basis for new drug on the therapy of DN.

糖尿病肾病（DN）是导致终末期肾病的重要原因，目前对DN的防治措施作用有限。DN的致病因素可通过活化哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）通路、抑制自噬而促进DN的进展，因此，mTORC1及其调控的细胞自噬已成为治疗DN的新靶点。前期研究中，我们已证实黄芪缓解DN大鼠蛋白尿、减少足细胞凋亡与其改善内质网应激有关。鉴于内质网应激与细胞自噬的相互调控作用，我们提出黄芪通过下调mTORC1信号通路，活化自噬，延缓DN进展的假说。本研究采用链脲佐菌素诱导的DN大鼠为模型，分别给予黄芪、黄芪甲苷或黄芪多糖干预，观察糖尿病肾病大鼠肾脏病变、mTORC1信号通路及自噬的变化；采用衣霉素诱导内质网应激或mTORC1活化剂阻断自噬的足细胞为模型，观察黄芪甲苷和黄芪多糖对足细胞mTORC1信号通路、自噬活性的影响，阐明黄芪治疗DN的分子机制，为治疗DN的新药开发提供理论依据。