Diacylglycerol Kinase alpha is Involved in the Vitamin E-Induced Amelioration of Diabetic Nephropathy in Mice.
Diacylglycerol Kinase alpha is Involved in the Vitamin E-Induced Amelioration of Diabetic Nephropathy in Mice.
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DOI：
10.1038/s41598-017-02354-3
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发表时间：
2017-06-01
影响因子：
4.6
通讯作者：
Shirai Y
中科院分区：
文献类型：
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作者：
Hayashi D;Yagi K;Song C;Ueda S;Yamanoue M;Topham M;Suzaki T;Saito N;Emoto N;Shirai Y
糖尿病肾病（diabetic nephropathy，DN）是糖尿病的血管并发症之一，是由糖尿病高血糖时甘油二酯（diacylglycerol，DG）生成增多导致蛋白激酶C（proteinkinaseC，PKC）异常激活而引起的。二酰基甘油激酶（DGK）将DG转化为磷脂酸。因此，预期DGK的活化将改善DN。事实上，已有报道维生素E（VtE）通过激活DGK改善大鼠DN，我们最近报道VtE在体外特异性激活DGKα亚型。然而，DGKα是否参与了体内VtE诱导的DN改善仍不清楚。因此，我们在野生型（DGKα+/+）和DGKα缺陷型（DGKα−/−）小鼠中研究了VtE诱导的DN改善，其中糖尿病是由链脲佐菌素诱导的。在DGKα+/+小鼠中，VtE治疗改善了DN的几种症状，但在DGKα−/−小鼠中没有改善。此外，肾小球的透射电子显微镜检查和肾小球上皮细胞（足细胞）的免疫荧光染色表明，VtE改善了DGKα+/+小鼠的足细胞病理学并防止了足细胞丢失，但在DGKα−/−小鼠中没有。我们发现VtE可以改善小鼠的DN，并且DGKα参与了VtE诱导的体内DN改善，这表明DGKα是一个有吸引力的DN治疗靶点。
Diabetic nephropathy (DN) is one of vascular complications of diabetes and is caused by abnormal protein kinase C activation as a result of increased diacylglycerol (DG) production in diabetic hyperglycaemia. Diacylglycerol kinase (DGK) converts DG into phosphatidic acid. Therefore, it is expected that the activation of DGK would ameliorate DN. Indeed, it has been reported that vitamin E (VtE) ameliorates DN in rat by activating DGK, and we recently reported that VtE specifically activates DGKα isoform in vitro. However, whether DGKα is involved in the VtE-induced amelioration of DN in vivo remains unknown. Therefore, we investigated the VtE-induced amelioration of DN in wild-type (DGKα+/+) and DGKα–deficient (DGKα−/−) mice in which diabetes was induced by streptozocin. Several symptoms of DN were ameliorated by VtE treatment in the DGKα+/+ mice but not in the DGKα−/− mice. Moreover, transmission electron microscopy of glomeruli and immunofluorescent staining of glomerular epithelial cells (podocytes) indicated that VtE ameliorates podocyte pathology and prevents podocyte loss in the DGKα+/+ mice but not in the DGKα−/− mice. We showed that VtE can ameliorate DN in mice and that DGKα is involved in the VtE-induced amelioration of DN in vivo, suggesting that DGKα is an attractive therapeutic target for DN.