TRPC6 channel activation promotes neonatal glomerular mesangial cell apoptosis via calcineurin/NFAT and FasL/Fas signaling pathways.
TRPC6 channel activation promotes neonatal glomerular mesangial cell apoptosis via calcineurin/NFAT and FasL/Fas signaling pathways.
复制标题
DOI：
10.1038/srep29041
复制
发表时间：
2016-07-07
影响因子：
4.6
通讯作者：
Adebiyi A
中科院分区：
文献类型：
--
作者：
Soni H;Adebiyi A
肾小球系膜细胞（GMC）的增殖和死亡参与了肾小球疾病的发病机制。控制GMC存活的机制知之甚少，但可能包括由细胞内Ca 2+（[Ca 2 +]i）浓度变化调节的信号转导途径。在这项研究中，我们调查是否激活经典瞬时受体电位（TRPC）6通道和连续的[Ca 2 +]i升高改变新生儿GMC的生存。在原代新生猪GMCs中，穿孔素（HF）诱导的TRPC 6通道激活增加[Ca 2 +]i浓度，抑制增殖，并引发细胞凋亡。HF诱导的新生GMC凋亡与氧化应激无关。然而，HF诱导的TRPC 6通道激活刺激活化T细胞的核因子胞质1（NFATc 1）的核转位。HF还增加细胞死亡表面受体Fas配体（FasL）水平和细胞中的半胱天冬酶-8活性;[Ca 2 +]i螯合剂BAPTA、钙调神经磷酸酶/NFAT抑制剂VIVIT和TRPC 6通道敲低减轻了这种作用。因此，HF诱导的新生GMC凋亡减弱BAPTA，VIVIT，Fas阻断抗体，和caspase-3/7抑制剂。这些发现表明TRPC 6通道依赖性[Ca 2 +]i升高和随后的钙调神经磷酸酶/NFAT、FasL/Fas和半胱天冬酶信号级联的诱导促进新生猪GMC凋亡。
Glomerular mesangial cell (GMC) proliferation and death are involved in the pathogenesis of glomerular disorders. The mechanisms that control GMC survival are poorly understood, but may include signal transduction pathways that are modulated by changes in intracellular Ca2+ ([Ca2+]i) concentration. In this study, we investigated whether activation of the canonical transient receptor potential (TRPC) 6 channels and successive [Ca2+]i elevation alter neonatal GMC survival. Hyperforin (HF)-induced TRPC6 channel activation increased [Ca2+]i concentration, inhibited proliferation, and triggered apoptotic cell death in primary neonatal pig GMCs. HF-induced neonatal GMC apoptosis was not associated with oxidative stress. However, HF-induced TRPC6 channel activation stimulated nuclear translocation of the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1). HF also increased cell death surface receptor Fas ligand (FasL) level and caspase-8 activity in the cells; effects mitigated by [Ca2+]i chelator BAPTA, calcineurin/NFAT inhibitor VIVIT, and TRPC6 channel knockdown. Accordingly, HF-induced neonatal GMC apoptosis was attenuated by BAPTA, VIVIT, Fas blocking antibody, and a caspase-3/7 inhibitor. These findings suggest that TRPC6 channel-dependent [Ca2+]i elevation and the ensuing induction of the calcineurin/NFAT, FasL/Fas, and caspase signaling cascades promote neonatal pig GMC apoptosis.