Klotho inhibits PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy
Klotho inhibits PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy
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Klotho 抑制 PKC α/p66SHC 介导的糖尿病肾病足细胞损伤
DOI：
10.1016/j.mce.2019.110490
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发表时间：
2019-08-20
影响因子：
4.1
通讯作者：
Zhao, Jinghong
中科院分区：
文献类型：
--
作者：
Jiang, Wei;Xiao, Tangli;Zhao, Jinghong
糖尿病肾病是一种进行性疾病，其主要病因是足细胞损伤。据报道，蛋白激酶C亚型α（PKC alpha）作为一种参与足细胞损伤的钙依赖性丝/苏蛋白激酶，可以调节p66 SHC的磷酸化。然而，PKC α/p66 SHC在DN中的作用尚不清楚。Klotho是一种抗衰老蛋白，在保护肾脏方面具有关键作用，主要在肾脏中表达并在血液中分泌。尽管如此，Klotho改善DN足细胞损伤的机制仍不清楚。我们的数据显示，Klotho在STZ治疗的小鼠中降低，并且在糖尿病KL +/-小鼠中进一步降低。正如预期的那样，Klotho缺乏加重了糖尿病诱导的蛋白尿和足细胞损伤，伴随着PKC α和p66 SHC的激活。相反，Klotho的过度表达部分改善了PKC α/p66 SHC介导的足细胞损伤和蛋白尿。此外，体外实验表明，高糖诱导的足细胞凋亡与PKC α的激活及随后细胞内活性氧（ROS）的增加有关，Klotho可部分逆转高糖诱导的足细胞凋亡。因此，我们得出结论，Klotho可能抑制糖尿病肾病中PKC α/p66 SHC介导的足细胞损伤。
Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury. As a calcium-dependent serine/threonine protein kinase involved in podocyte injury, protein kinase C isoform alpha (PKC alpha) was reported to regulate the phosphorylation of p66SHC. However, the role of PKC alpha/p66SHC in DN remains unknown. Klotho, an anti-aging protein with critical roles in protecting kidney, is expressed predominantly in the kidney and secreted in the blood. Nonetheless, the mechanism underlying amelioration of podocyte injury by Klotho in DN remains unclear. Our data showed that Klotho was decreased in STZ-treated mice and was further declined in diabetic KL +/- mice. As expected, Klotho deficiency aggravated diabetes-induced proteinuria and podocyte injury, accompanied by the activation of PKC alpha and p66SHC. In contrast, overexpression of Klotho partially ameliorated PKC alpha/p66SHC-mediated podocyte injury and proteinuria. In addition, in vitro experiments showed that activation of PKC alpha and subsequently increased intracellular reactive oxygen species (ROS) was involved in podocytic apoptosis induced by high glucose (HG), which could be partially reversed by Klotho. Hence, we conclude that Klotho might inhibit PKC alpha/p66SHC-mediated podocyte injury in diabetic nephropathy.