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蛋白聚糖 syndecan 4 通过 RhoA/Rho 相关蛋白激酶信号通路调节瞬时受体电位经典型 6 通道。

The proteoglycan syndecan 4 regulates transient receptor potential canonical 6 channels via RhoA/Rho-associated protein kinase signaling.

机构信息

Odense University Hospital and University of Southern Denmark, Institute for Molecular Medicine, Cardiovascular and Renal Research, Institute of Clinical Research, Winsløwparken 21.3, DK-5000 Odense C, Denmark.

出版信息

Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):378-85. doi: 10.1161/ATVBAHA.111.241018. Epub 2011 Dec 8.

DOI:10.1161/ATVBAHA.111.241018
PMID:22155451
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3881556/
Abstract

OBJECTIVE

Syndecan 4 (Sdc4) modulates signal transduction and regulates activity of protein channels. Sdc4 is essential for the regulation of cellular permeability. We hypothesized that Sdc4 may regulate transient receptor potential canonical 6 (TRPC6) channels, a determinant of glomerular permeability, in a RhoA/Rho-associated protein kinase-dependent manner.

METHODS AND RESULTS

Sdc4 knockout (Sdc4(-/-)) mice showed increased glomerular filtration rate and ameliorated albuminuria under baseline conditions and after bovine serum albumin overload (each P<0.05). Using reverse transcription-polymerase chain reaction and immunoblotting, Sdc4(-/-) mice showed reduced TRPC6 mRNA by 79% and TRPC6 protein by 82% (each P<0.05). Sdc4(-/-) mice showed an increased RhoA activity by 87% and increased phosphorylation of ezrin in glomeruli by 48% (each P<0.05). Sdc4 knockdown in cultured podocytes reduced TRPC6 gene expression and reduced the association of TRPC6 with plasma membrane and TRPC6-mediated calcium influx and currents. Sdc4 knockdown inactivated negative regulatory protein Rho GTPase activating protein by 33%, accompanied by a 41% increase in RhoA activity and increased phosphorylation of ezrin (P<0.05). Conversely, overexpression of Sdc4 reduced RhoA activity and increased TRPC6 protein and TRPC6-mediated calcium influx and currents.

CONCLUSIONS

Our results establish a previously unknown function of Sdc4 for regulation of TRPC6 channels and support the role of Sdc4 for the regulation of glomerular permeability.

摘要

目的

连接蛋白 4（Sdc4）调节信号转导并调节蛋白通道的活性。Sdc4 是调节细胞通透性所必需的。我们假设 Sdc4 可能通过 RhoA/ Rho 相关蛋白激酶依赖性方式调节瞬时受体电位经典型 6（TRPC6）通道，该通道是肾小球通透性的决定因素。

方法和结果

Sdc4 敲除（Sdc4(-/-)）小鼠在基础条件下和牛血清白蛋白过载后显示出肾小球滤过率增加和白蛋白尿改善（均 P<0.05）。通过逆转录聚合酶链反应和免疫印迹，Sdc4(-/-)小鼠显示 TRPC6 mRNA 减少 79%，TRPC6 蛋白减少 82%（均 P<0.05）。Sdc4(-/-)小鼠显示 RhoA 活性增加 87%，肾小球中 ezrin 磷酸化增加 48%（均 P<0.05）。在培养的足细胞中敲低 Sdc4 减少了 TRPC6 基因表达，并减少了 TRPC6 与质膜的结合以及 TRPC6 介导的钙内流和电流。Sdc4 敲低使负调节蛋白 Rho GTP 酶激活蛋白失活 33%，同时 RhoA 活性增加 41%，ezrin 磷酸化增加 41%（P<0.05）。相反，Sdc4 的过表达降低了 RhoA 活性，增加了 TRPC6 蛋白和 TRPC6 介导的钙内流和电流。

结论

我们的结果确立了 Sdc4 调节 TRPC6 通道的先前未知功能，并支持 Sdc4 调节肾小球通透性的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/19abadeaa159/nihms540955f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/cc818cd9361c/nihms540955f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/a4cd31007da7/nihms540955f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/2048b06595ac/nihms540955f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/dec5c12c9748/nihms540955f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/19abadeaa159/nihms540955f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/cc818cd9361c/nihms540955f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/a4cd31007da7/nihms540955f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/2048b06595ac/nihms540955f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/dec5c12c9748/nihms540955f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8950/3881556/19abadeaa159/nihms540955f5.jpg

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