Mangiferin prevents diabetic nephropathy progression and protects podocyte function via autophagy in diabetic rat glomeruli
Mangiferin prevents diabetic nephropathy progression and protects podocyte function via autophagy in diabetic rat glomeruli
复制标题
芒果苷通过糖尿病大鼠肾小球的自噬预防糖尿病肾病进展并保护足细胞功能
DOI：
10.1016/j.ejphar.2018.02.009
复制
发表时间：
2018-04-05
影响因子：
5
通讯作者：
Li, Ling
中科院分区：
文献类型：
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作者：
Wang, Xiaodan;Gao, Lihui;Li, Ling
糖尿病肾病是糖尿病最严重的微血管病变之一，是导致终末期肾病的主要原因。大量研究表明，足细胞损伤与进行性蛋白尿有关。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中起着关键作用。自噬功能受损参与了糖尿病肾病足细胞丢失的发病机制，导致大量蛋白尿。本研究旨在探讨芒果苷对链脲佐菌素(STZ)诱导的糖尿病大鼠肾脏病变的影响，重点探讨与足细胞自噬相关的病理因素及AMPK-mTOR-ULK1信号转导途径。结果表明，芒果苷可明显减少糖尿病大鼠的蛋白尿，抑制肾小球细胞外基质的扩张，恢复足细胞标志物neparin的表达，提示芒果苷可延缓糖尿病肾病的进程，对足细胞具有保护作用。此外，芒果苷还诱导了自噬，表现为糖尿病肾病大鼠和足细胞中Lc3 II的上调和p62的下调。透射电子显微镜分析显示，芒果苷可增加糖尿病肾病大鼠足细胞自噬小体的数量。这一机制与AMPK磷酸化上调、mTOR磷酸化下调和p-ULK1上调有关。综上所述，芒果苷通过AMPK-mTOR-ULK1途径增强糖尿病条件下的自噬，延缓了糖尿病肾病的进展，并保护了足细胞。这些发现为芒果苷对糖尿病肾病肾脏保护作用的分子机制提供了新的见解。
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.