Cannabinoid Receptor 2 Expression in Human Proximal Tubule Cells is Regulated by Albumin Independent of ERK1/2 Signaling
Cannabinoid Receptor 2 Expression in Human Proximal Tubule Cells is Regulated by Albumin Independent of ERK1/2 Signaling
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DOI：
10.1159/000354529
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发表时间：
2013-01-01
影响因子：
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通讯作者：
Hryciw, Deanne H.
中科院分区：
文献类型：
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作者：
Jenkin, Kayte A.;McAinch, Andrew J.;Hryciw, Deanne H.
背景：大麻素2型受体(CB2)在动物和人类2型糖尿病(T2 DM)患者的足细胞中表达减少，CB2的激活可改善动物的蛋白尿。由于蛋白尿也是由近端小管功能障碍引起的，本研究的目的是研究CB2在糖尿病条件下的肾小管表达，以及这些变化背后的细胞信号通路。方法：对糖尿病动物模型和人肾2细胞(HK2)在白蛋白和葡萄糖水平升高时CB2总蛋白、CB2mRNA和蛋白水平进行了研究。我们还使用Latrunculin来确定是否需要白蛋白内化来调节CB2水平。最后，我们表征了白蛋白对AKT活性和总AKT、ERK1/2和p38的反应水平。结果：糖尿病大鼠肾组织中CB2的表达无明显变化。在HK2细胞中，CB2的表达在高糖暴露后没有改变。高白蛋白单独处理和联合高糖处理，导致CB2受体在6小时和18小时的表达显著降低。在高白蛋白和高糖联合作用下，CB2蛋白的表达在6小时和24小时明显降低。白蛋白需要内化来调节CB2水平，抑制ERK1/2并不能挽救白蛋白反应中CB2的丢失。结论：在体外实验中，白蛋白内化是降低近曲小管CB2mRNA和蛋白表达的必要条件。因此，CB2在足细胞和肾小管中的表达改变可能是T2 DM蛋白尿的原因之一。版权所有(C)2013 S.Karger AG，巴塞尔
Background: The cannabinoid receptor type 2 (CB2) is reduced in podocytes of animals and humans with Type 2 Diabetes Mellitus (T2DM), with activation of CB2 ameliorating albuminuria in animals. As albuminuria also is due to proximal tubule dysfunction, the aim of this study is to investigate tubular expression of CB2 under diabetic conditions in addition to the cell signaling pathways that underlie these changes. Methods: We characterized total CB2 protein in diabetic animals and in Human Kidney 2 (HK2) cells exposed to elevated albumin and glucose, the levels of CB2 mRNA and protein. We also used latrunculin to determine if internalization of albumin was required to regulate CB2 levels. Finally, we characterized the levels of active and total AKT, ERK1/2 and p38 in response to albumin. Results: There were no changes to CB2 expression in kidney lysate from diabetic rats. In HK2 cells, expression of CB2 was unaltered following exposure to high glucose. High albumin treatment alone and in combination with high glucose, resulted in a significant reduction in CB2 receptor mRNA expression at 6 and 18 hours. CB2 protein expression was reduced at 6 and 24 hours, in high albumin and in combination with high glucose. Internalization of albumin was required to regulate CB2 levels, and inhibition of ERK1/2, did not rescue the loss of CB2 in response to albumin. Conclusion: We have demonstrated that internalization of albumin is required to reduce CB2 mRNA and protein expression in proximal tubules in vitro. Consequently, altered expression of CB2 in both the podocytes and tubules may contribute to the albuminuria observed in T2DM. Copyright (C) 2013 S. Karger AG, Basel