(Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose
(Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose
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DOI：
10.1152/ajpendo.00603.2014
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发表时间：
2015-08-01
影响因子：
5.1
通讯作者：
Siragy, Helmy M.
中科院分区：
文献类型：
--
作者：
Li, Caixia;Siragy, Helmy M.
高糖可减少足细胞的自噬并增强其凋亡。以前，我们报道了高葡萄糖通过上调（原）肾素受体（PRR）诱导足细胞损伤。我们假设，增加PRR减少自噬和增加小鼠足细胞暴露于高葡萄糖通过激活PI 3 K/Akt/mTOR信号通路的凋亡。将小鼠足细胞在正常（5 mmol/l）或高（25 mmol/l）D-葡萄糖中培养48 h。高糖显著增加PRR的mRNA和蛋白水平，PI 3 K/Akt/mTOR和p62的磷酸化。相比之下，高葡萄糖通过磷酸化Ser 757和微管相关蛋白-1轻链3B（LC 3B）-II和Lamp-2的蛋白水平降低了ERK-51样激酶-1（ULK 1）的活化。巴弗洛霉素A1增加高糖处理的细胞中LC 3BII和p62的积累。高糖降低自噬通量。共聚焦显微镜研究显示，响应于高葡萄糖，LC 3B的蛋白水平显著降低。Cyto-ID自噬染色显示高葡萄糖下自噬体形成显著减少。在不存在PRR的情况下，用sc-79激活Akt或用MHY-1485激活mTOR增加了p62积累。TUNEL法检测Caspase-3/7活性和凋亡在高糖处理的足细胞中显著增加。PRR siRNA显著逆转了高糖的作用。基于这些数据，我们得出结论，高葡萄糖通过PRR/PI 3 K/Akt/mTOR信号通路减少小鼠足细胞的自噬并增加其凋亡。
High glucose reduces autophagy and enhances apoptosis of podocytes. Previously, we reported that high glucose induced podocyte injury through upregulation of the (pro)renin receptor (PRR). We hypothesized that increasing PRR reduces autophagy and increases apoptosis of mouse podocytes exposed to high glucose via activation of the PI3K/Akt/mTOR signaling pathway. Mouse podocytes were cultured in normal (5 mmol/l) or high (25 mmol/l) D-glucose for 48 h. High glucose significantly increased mRNA and protein levels of PRR, phosphorylation of PI3K/Akt/mTOR, and p62. In contrast, high glucose decreased activation of UNC-51-like kinase-1 (ULK1) by phosphorylating Ser757 and protein levels of microtubule-associated protein-1 light chain 3B (LC3B)-II and Lamp-2. Bafilomycin A1 increased LC3BII and p62 accumulation in high-glucose-treated cells. High glucose reduced the autophagic flux. Confocal microscopy studies showed significant reduction in the protein level of LC3B in response to high glucose. Cyto-ID autophagy staining showed a significant decrease in autophagosome formation with high glucose. In the absence of PRR, activation of Akt with sc-79 or mTOR with MHY-1485 increased p62 accumulation. Caspase-3/7 activity and apoptosis monitored by TUNEL assay were significantly increased in podocytes treated with high glucose. PRR siRNA significantly reversed the effects of high glucose. Based on these data, we conclude that high glucose decreases autophagy and increases apoptosis in mouse podocytes through the PRR/PI3K/Akt/mTOR signaling pathway.