A novel mechanism of action for salidroside to alleviate diabetic albuminuria: effects on albumin transcytosis across glomerular endothelial cells
A novel mechanism of action for salidroside to alleviate diabetic albuminuria: effects on albumin transcytosis across glomerular endothelial cells
复制标题
红景天苷缓解糖尿病蛋白尿的新作用机制：对肾小球内皮细胞白蛋白转胞吞作用的影响
DOI：
10.1152/ajpendo.00391.2015
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发表时间：
2016-02-01
影响因子：
5.1
通讯作者：
Jin, Si
中科院分区：
文献类型：
--
作者：
Wu, Dan;Yang, Xiaoyan;Jin, Si
红景天苷（SAL）是从药用植物红景天中分离得到的一种苯乙醇苷。R.据报道，玫瑰花对糖尿病肾病（DN）和高葡萄糖（HG）诱导的系膜细胞增殖具有有益作用。鉴于小窝蛋白-1（Cav-1）在白蛋白跨内皮屏障转胞吞中的重要作用，本研究旨在阐明SAL是否能抑制Cav-1磷酸化，减少白蛋白跨肾小球内皮细胞（GECs）转胞吞，从而减轻糖尿病白蛋白尿，并探讨其上游信号通路。为了评估SAL的治疗潜力和参与DN蛋白尿的机制，我们将SAL口服给药于db/db小鼠，并测量SAL对蛋白尿的影响。在一个新建立的体外细胞模型中探索了白蛋白跨GECs的转胞吞作用。在db/db小鼠中，SAL处理后白蛋白与肌酐的比值显著降低。SAL降低正常血糖和高血糖条件下GEC中白蛋白的胞吞转运。SAL可逆转HG诱导的AMP活化蛋白激酶的下调和Src激酶的上调，并阻断Cav-1磷酸化的上调。同时，SAL降低线粒体超氧阴离子的产生，并使线粒体膜电位中度去极化。我们的结论是，SAL发挥其蛋白尿缓解作用下调Cav-1磷酸化和抑制白蛋白转胞吞跨GECs。这些研究提供了第一个证据，干扰白蛋白转胞吞跨GEC作为一种新的方法来治疗糖尿病蛋白尿。
Salidroside (SAL) is a phenylethanoid glycoside isolated from the medicinal plant Rhodiola rosea. R. rosea has been reported to have beneficial effects on diabetic nephropathy (DN) and high-glucose (HG)-induced mesangial cell proliferation. Given the importance of caveolin-1 (Cav-1) in transcytosis of albumin across the endothelial barrier, the present study was designed to elucidate whether SAL could inhibit Cav-1 phosphorylation and reduce the albumin transcytosis across glomerular endothelial cells (GECs) to alleviate diabetic albuminuria as well as to explore its upstream signaling pathway. To assess the therapeutic potential of SAL and the mechanisms involved in DN albuminuria, we orally administered SAL to db/db mice, and the effect of SAL on the albuminuria was measured. The albumin transcytosis across GECs was explored in a newly established in vitro cellular model. The ratio of albumin to creatinine was significantly reduced upon SAL treatment in db/db mice. SAL decreased the albumin transcytosis across GECs in both normoglycemic and hyperglycemic conditions. SAL reversed the HG-induced downregulation of AMP-activated protein kinase and upregulation of Src kinase and blocked the upregulation Cav-1 phosphorylation. Meanwhile, SAL decreased mitochondrial superoxide anion production and moderately depolarized mitochondrial membrane potential. We conclude that SAL exerts its proteinuria-alleviating effects by downregulation of Cav-1 phosphorylation and inhibition of albumin transcytosis across GECs. These studies provide the first evidence of interference with albumin transcytosis across GECs as a novel approach to the treatment of diabetic albuminuria.