Wnt/ß-catenin signalling pathway mediates high glucose induced cell injury through activation of TRPC6 in podocytes
Wnt/ß-catenin signalling pathway mediates high glucose induced cell injury through activation of TRPC6 in podocytes
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DOI：
10.1111/cpr.12010
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发表时间：
2013-02-01
影响因子：
8.5
通讯作者：
Yang, Z.
中科院分区：
文献类型：
--
作者：
Li, Z.;Xu, J.;Yang, Z.
糖尿病肾病是糖尿病的主要并发症，也是终末期肾脏疾病的常见原因，最近的研究表明足细胞损伤可能在其发病机制中起作用。糖尿病肾病早期有足细胞脱落，这被认为会引起肾小球蛋白尿和随后的肾小球损伤；然而，其潜在的分子机制仍然知之甚少。在这里，我们报告了我们验证了一个假设，即早期糖尿病足细胞损伤至少部分是由小鼠足细胞中瞬时受体电位阳离子通道6 （TRPC6）的上调引起的，TRPC6受典型Wnt信号通路的调节。材料与方法采用MTT、流式细胞术、实时定量PCR、western blot等方法研究高浓度d -葡萄糖（HG, 30 mM）诱导小鼠足细胞损伤的机制。结果HG诱导足细胞凋亡，降低分化足细胞活力。它在小鼠足细胞中引起TRPC6的时间依赖性上调和典型Wnt信号通路的激活。在这些细胞中，dickkopf相关蛋白1 （Dkk1）阻断Wnt信号通路可有效降低TRPC6上调，改善足细胞凋亡。此外，用Dkk1处理可以减轻HG引起的细胞活力降低。结论Wnt/ β -catenin信号通路可能在trpc6介导的糖尿病足细胞损伤的发病机制中具有潜在的活性。
Objectives Diabetic nephropathy is a major complication of diabetes and a frequent cause of end-stage renal disease and recent studies suggest that podocyte damage may play a role in the pathogenesis of this. At early onset of diabetic nephropathy there is podocyte drop-out, which is thought to provoke glomerular albuminuria and subsequent glomerular injury; however, the underlying molecular mechanisms of this remain poorly understood. Here we report that we tested the hypothesis that early diabetic podocyte injury is caused, at least in part, by up-regulation of transient receptor potential cation channel 6 (TRPC6), which is regulated by the canonical Wnt signalling pathway, in mouse podocytes.Materials and methods Mechanism of injury initiation in mouse podocytes, by high concentration of D-glucose (HG, 30 mM), was investigated by MTT, flow cytometry, real-time quantitative PCR, and western blot analysis.Results HG induced apoptosis and reduced viability of differentiated podocytes. It caused time-dependent up-regulation of TRPC6 and activation of the canonical Wnt signalling pathway, in mouse podocytes. In these cells, blockade of the Wnt signalling pathway by dickkopf related protein 1 (Dkk1) resulted in effective reduction of TRPC6 up-regulation and amelioration of podocyte apoptosis. Furthermore, reduction of cell viability induced by HG was attenuated by treatment with Dkk1.Conclusion These findings indicate that the Wnt/beta-catenin signalling pathway may potentially be active in pathogenesis of TRPC6-mediated diabetic podocyte injury.