α1-肾上腺素能受体激活通过瞬时受体电位阳离子通道6（TRPC6）通道刺激培养的人系膜细胞中的钙内流和增殖。

Alpha1-Adrenergic Receptor Activation Stimulates Calcium Entry and Proliferation via TRPC6 Channels in Cultured Human Mesangial Cells.

作者信息

Kong Fanwu, Ma Linlin, Zou Li, Meng Kexin, Ji Tianrong, Zhang Lei, Zhang Rui, Jiao Jundong

机构信息

Department of Nephrology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China.

出版信息

Cell Physiol Biochem. 2015;36(5):1928-38. doi: 10.1159/000430161. Epub 2015 Jul 17.

DOI:10.1159/000430161

PMID:26202353

Abstract

BACKGROUND AND AIMS

There is accumulating evidence that sympathetic nervous hyperactivity contributes to the pathogenesis of glomerular sclerosis independent of blood pressure effects. A previous study showed that α1-adrenoceptor (α1-AR) antagonists inhibit mesangial cell (MC) proliferation. However, the underlying mechanism remains unclear.

METHODS AND RESULTS

We found that α1-AR is expressed in a human mesangial cell line. The α1-AR agonist phenylephrine (PE) induced Ca(2+) influx as well as release from intracellular Ca(2+) stores. Blockade of TRPC6 with siRNA, anti-TRPC6 antibodies and a TRPC blocker attenuated the PE-induced [Ca(2+)]i increase. Additionally, the PE-induced [Ca(2+)]i increase was phospholipase C dependent. Furthermore, PE induced a [Ca(2+)]i increase even when the intracellular Ca(2+) stores were already depleted. This effect was mimicked by an analog of diacylglycerol. These results suggested that, upon α1-AR stimulation, TRPC6 mediates Ca(2+) influx via a receptor-operated Ca(2+) entry mechanism. Finally, TRPC6 contributes to the PE-induced MC proliferation. The mechanisms are associated with the extracellular signal-regulated kinase (ERK) signaling pathway because blockade of TRPC6 and chelation of extracellular Ca(2+) abrogated PE-induced ERK1/2 abrogated PE-induced ERK1/2 phosphorylation.

CONCLUSION

TRPC6 channels are involved in α1-AR activation-induced Ca(2+) entry, which mediates proliferation via ERK signaling in human MCs.

摘要

背景与目的

越来越多的证据表明，交感神经活动亢进在不依赖血压影响的情况下参与肾小球硬化的发病机制。先前的一项研究表明，α1肾上腺素能受体（α1-AR）拮抗剂可抑制系膜细胞（MC）增殖。然而，其潜在机制仍不清楚。

方法与结果

我们发现α1-AR在人系膜细胞系中表达。α1-AR激动剂去氧肾上腺素（PE）可诱导Ca(2+)内流以及细胞内Ca(2+)储存库的释放。用小干扰RNA、抗TRPC6抗体和TRPC阻滞剂阻断TRPC6可减弱PE诱导的[Ca(2+)]i升高。此外，PE诱导的[Ca(2+)]i升高依赖于磷脂酶C。此外，即使细胞内Ca(2+)储存库已经耗尽，PE仍可诱导[Ca(2+)]i升高。二酰基甘油类似物可模拟这种效应。这些结果表明，在α1-AR刺激后，TRPC6通过受体操纵的Ca(2+)内流机制介导Ca(2+)内流。最后，TRPC6促进PE诱导的MC增殖。其机制与细胞外信号调节激酶（ERK）信号通路有关，因为阻断TRPC6和螯合细胞外Ca(2+)可消除PE诱导的ERK1/2磷酸化，而PE诱导的ERK1/2磷酸化可消除PE诱导的ERK1/2磷酸化。