Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-induced podocyte injury.
Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-induced podocyte injury.
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自噬通过保护高血糖诱导的荚膜细胞损伤，减轻糖尿病肾小球损伤。
DOI：
10.1371/journal.pone.0060546
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Fang L;Zhou Y;Cao H;Wen P;Jiang L;He W;Dai C;Yang J
尽管近来人们关注自噬在维持足细胞动态平衡中的重要作用，但对糖尿病状态下自噬在足细胞功能障碍中的变化和机制知之甚少。在这项研究中，我们研究了自噬在足细胞生物学中的作用及其在糖尿病肾病发病机制中的作用。足细胞具有较高的基础自噬水平。3-甲基腺嘌呤(3-MA)或Beclin-1 siRNA对基础自噬的抑制作用均不利于其结构。然而，在体内糖尿病和体外高糖条件下，足细胞高基础水平的自噬变得有缺陷，并且有缺陷的自噬促进了足细胞的损伤。由于内质网(ER)的动力学似乎在调节自噬通量中起着至关重要的作用，Salubrina/TUDCA(TUDCA)可以恢复有缺陷的自噬的结果进一步表明，自噬的演变可能是由ER应激中细胞保护输出的变化所介导的。最后，我们在体内证明了糖尿病状态下足细胞的自噬受到抑制，TUDCA可以改善缺陷自噬。综上所述，这些数据提示，由于高糖诱导的无缓解应激导致内质网细胞保护能力的丧失，自噬可能被中断，自噬缺陷可能加速糖尿病肾病的不可修复的进展。
Despite the recent attention focused on the important role of autophagy in maintaining podocyte homeostasis, little is known about the changes and mechanisms of autophagy in podocyte dysfunction under diabetic condition. In this study, we investigated the role of autophagy in podocyte biology and its involvement in the pathogenesis of diabetic nephropathy. Podocytes had a high basal level of autophagy. And basal autophagy inhibition either by 3-methyladenenine (3-MA) or by Beclin-1 siRNA was detrimental to its architectural structure. However, under diabetic condition in vivo and under high glucose conditions in vitro, high basal level of autophagy in podocytes became defective and defective autophagy facilitated the podocyte injury. Since the dynamics of endoplasmic reticulum(ER) seemed to play a vital role in regulating the autophagic flux, the results that Salubrinal/Tauroursodeoxycholic acid (TUDCA) could restore defective autophagy further indicated that the evolution of autophagy may be mediated by the changes of cytoprotective output in the ER stress. Finally, we demonstrated in vivo that the autophagy of podocyte was inhibited under diabetic status and TUDCA could improve defective autophagy. Taken together, these data suggested that autophagy might be interrupted due to the failure of ER cytoprotective capacity upon high glucose induced unmitigated stress, and the defective autophagy might accelerate the irreparable progression of diabetic nephropathy.
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