Yi Mixuan, Zhang Lei, Liu Yu, Livingston Man J, Chen Jian-Kang, Nahman N Stanley, Liu Fuyou, Dong Zheng
Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; and.
Am J Physiol Renal Physiol. 2017 Jul 1;313(1):F74-F84. doi: 10.1152/ajprenal.00114.2017. Epub 2017 Apr 12.
Podocytes are highly differentiated epithelial cells wrapping glomerular capillaries to form the filtration barrier in kidneys. As such, podocyte injury or dysfunction is a critical pathogenic event in glomerular disease. Autophagy plays an important role in the maintenance of the homeostasis and function of podocytes. However, it is less clear whether and how autophagy contributes to podocyte injury in glomerular disease. Here, we have examined the role of autophagy in adriamycin-induced nephropathy, a classic model of glomerular disease. We show that autophagy was induced by adriamycin in cultured podocytes in vitro and in podocytes in mice. In cultured podocytes, activation of autophagy with rapamycin led to the suppression of adriamycin-induced apoptosis, whereas inhibition of autophagy with chloroquine enhanced podocyte apoptosis during adriamycin treatment. To determine the role of autophagy in vivo, we established an inducible podocyte-specific autophagy-related gene 7 knockout mouse model (Podo-Atg7-KO). Compared with wild-type littermates, Podo-Atg7-KO mice showed higher levels of podocyte injury, glomerulopathy, and proteinuria during adriamycin treatment. Together, these observations support an important role of autophagy in protecting podocytes under the pathological conditions of glomerular disease, suggesting the therapeutic potential of autophagy induction.
足细胞是高度分化的上皮细胞，包裹肾小球毛细血管以形成肾脏的滤过屏障。因此，足细胞损伤或功能障碍是肾小球疾病中的关键致病事件。自噬在维持足细胞的稳态和功能中起重要作用。然而，自噬是否以及如何导致肾小球疾病中的足细胞损伤尚不清楚。在这里，我们研究了自噬在阿霉素诱导的肾病（一种经典的肾小球疾病模型）中的作用。我们发现，阿霉素在体外培养的足细胞和小鼠足细胞中均可诱导自噬。在培养的足细胞中，雷帕霉素激活自噬可抑制阿霉素诱导的细胞凋亡，而氯喹抑制自噬则会增强阿霉素处理期间的足细胞凋亡。为了确定自噬在体内的作用，我们建立了一种可诱导的足细胞特异性自噬相关基因7敲除小鼠模型（Podo-Atg7-KO）。与野生型同窝小鼠相比，Podo-Atg7-KO小鼠在阿霉素处理期间表现出更高水平的足细胞损伤、肾小球病变和蛋白尿。总之，这些观察结果支持自噬在肾小球疾病病理条件下保护足细胞中的重要作用，提示诱导自噬具有治疗潜力。
