Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts
Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts
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DOI：
10.1515/hsz-2014-0289
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发表时间：
2015-06-01
影响因子：
3.7
通讯作者：
Huwiler, Andrea
中科院分区：
文献类型：
--
作者：
Schwalm, Stephanie;Timcheva, Tankica Maneva;Huwiler, Andrea
鞘氨醇激酶（SK）亚型SK-1和SK-2都能催化生物活性脂质分子鞘氨醇1-磷酸（S1P）的产生。然而，亚型特异性细胞功能在很大程度上是未知的。在这项研究中，我们研究了SK-2在野生型C57BL/6或SK-2敲除（SK2ko）小鼠的原代小鼠肾系膜细胞（mMC）和胚胎成纤维细胞（MEF）中的细胞功能。我们发现，与野生型细胞相比，SK2ko细胞表现出明显更高的增殖和迁移活性，同时经典的细胞外信号调节激酶（ERK）和PI3K/Akt级联反应以及小G蛋白RhoA的细胞活性增加。此外，我们检测到SK-2ko细胞中SK-1蛋白和S1P(3)受体mRNA表达上调。MEK抑制剂U0126和S1P 1/3受体拮抗剂VPC23019阻断了SK-2ko细胞增加的迁移。此外，S1P(3)ko系膜细胞在S1P刺激下表现出增殖行为降低和迁移速率降低，这表明S1P(3)受体的参与至关重要。总之，我们的数据表明SK-2对肾系膜细胞和成纤维细胞的细胞生长和迁移具有抑制作用，并且针对sk治疗增生性疾病需要亚型选择性抑制剂。
Both of the sphingosine kinase (SK) subtypes SK-1 and SK-2 catalyze the production of the bioactive lipid molecule sphingosine 1-phosphate (S1P). However, the subtype-specific cellular functions are largely unknown. In this study, we investigated the cellular function of SK-2 in primary mouse renal mesangial cells (mMC) and embryonic fibroblasts (MEF) from wild-type C57BL/6 or SK-2 knockout (SK2ko) mice. We found that SK2ko cells displayed a significantly higher proliferative and migratory activity when compared to wild-type cells, with concomitant increased cellular activities of the classical extracellular signal regulated kinase (ERK) and PI3K/Akt cascades, and of the small G protein RhoA. Furthermore, we detected an upregulation of SK-1 protein and S1P(3) receptor mRNA expression in SK-2ko cells. The MEK inhibitor U0126 and the S1P 1/3 receptor antagonist VPC23019 blocked the increased migration of SK-2ko cells. Additionally, S1P(3)ko mesangial cells showed a reduced proliferative behavior and reduced migration rate upon S1P stimulation, suggesting a crucial involvement of the S1P(3) receptor. In summary, our data demonstrate that SK-2 exerts suppressive effects on cell growth and migration in renal mesangial cells and fibroblasts, and that therapeutic targeting of SKs for treating proliferative diseases requires subtype-selective inhibitors.