Biomedical Engineering Research Center, Kunming Medical University, Kunming 650500, China; The Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, China.
Biomedical Engineering Research Center, Kunming Medical University, Kunming 650500, China.
Eur J Pharmacol. 2018 Apr 5;824:170-178. doi: 10.1016/j.ejphar.2018.02.009. Epub 2018 Feb 11.
Diabetic nephropathy (DN) is one of the most severe microangiopathies of diabetes mellitus and is a leading cause of end stage renal disease. Numerous studies suggest that podocyte injury contributes to progressive proteinuria. Podocytes are highly specialized, terminally differentiated cells that are unable to proliferate, autophagy plays a key role in maintaining the structure and function of podocytes. Autophagy impairment is involved in the pathogenesis of podocyte loss, which leads to massive proteinuria in DN. In the present study, we investigated the effects of mangiferin on nephropathy in streptozotocin (STZ)-induced diabetic rats; we focused on pathological factors related to autophagy in podocytes and the AMPK-mTOR-ULK1 pathway. The results showed that chronic treatment with mangiferin significantly decreased albuminuria, inhibited glomerular extracellular matrix expansion and restored the expression of nephrin, a podocyte marker, in diabetic rats; these results suggest that mangiferin delayed the process of DN and protected the podocytes. In addition, mangiferin induced autophagy, as shown by the up-regulation of LC3 II and the down-regulation of p62 in both DN rats and podocytes. Transmission electron microscope analyses showed that mangiferin increased the number of autophagosomes in the podocytes of DN rats. This underlying mechanism was associated with the up-regulation of AMPK phosphorylation, the down-regulation of mTOR phosphorylation and the up-regulation of p-ULK1. Taken together, mangiferin delayed the progression of DN and protected the podocytes by enhancing autophagy under diabetic conditions via the AMPK-mTOR-ULK1 pathway. These findings provide new insights into the molecular mechanisms underlying the renoprotective effects of mangiferin in DN.
糖尿病肾病（DN）是糖尿病最严重的微血管并发症之一，也是终末期肾病的主要原因。大量研究表明，足细胞损伤导致进行性蛋白尿。足细胞是高度特化的终末分化细胞，不能增殖，自噬在维持足细胞的结构和功能方面起着关键作用。自噬损伤参与了足细胞丢失的发病机制，导致 DN 患者大量蛋白尿。在本研究中，我们研究了芒果苷对链脲佐菌素（STZ）诱导的糖尿病大鼠肾病的影响；我们重点研究了与足细胞自噬相关的病理因素和 AMPK-mTOR-ULK1 通路。结果表明，芒果苷慢性治疗可显著减少白蛋白尿，抑制肾小球细胞外基质扩张，并恢复糖尿病大鼠足细胞标记物nephrin 的表达；这些结果表明芒果苷延缓了 DN 的进程并保护了足细胞。此外，芒果苷诱导自噬，表现为 LC3 II 的上调和 p62 在 DN 大鼠和足细胞中的下调。透射电子显微镜分析显示，芒果苷增加了 DN 大鼠足细胞中的自噬体数量。这种潜在机制与 AMPK 磷酸化的上调、mTOR 磷酸化的下调和 p-ULK1 的上调有关。总之，芒果苷通过 AMPK-mTOR-ULK1 通路增强自噬，延缓 DN 的进展并保护足细胞，为 DN 中芒果苷的肾保护作用的分子机制提供了新的见解。
