Signaling Mechanism Underlying the Promotion of Keratinocyte Migration by Angiotensin II
Signaling Mechanism Underlying the Promotion of Keratinocyte Migration by Angiotensin II
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DOI：
10.1124/mol.114.096461
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发表时间：
2015-02
影响因子：
3.6
通讯作者：
Hiroki Sakai;Kenji Matsuura;Yoshie Tanaka;Takeshi Honda;T. Nishida;M. Inui
中科院分区：
文献类型：
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作者：
Hiroki Sakai;Kenji Matsuura;Yoshie Tanaka;Takeshi Honda;T. Nishida;M. Inui
上皮再生在皮肤伤口愈合期间早期开始，并且由各种生长因子和细胞因子调节。血管紧张素II促进角质形成细胞的迁移，从而有助于伤口愈合。我们研究了血管紧张素II刺激人角质形成细胞迁移的机制。血管紧张素II诱导的角质形成细胞迁移受到血管紧张素II 1型受体（AT 1 R）拮抗剂（坎地沙坦）或血管紧张素II 2型受体（AT 2 R）拮抗剂（PD 123319）以及AT 1 R或AT 2 R耗竭的抑制。AT 1 R的偏向性激动剂[Sar 1，Ile 4，Ile 8]血管紧张素II诱导细胞迁移，而β-arrestin 2耗竭抑制血管紧张素II诱导的迁移。血管紧张素II诱导的迁移被转化生长因子-β（TGF-β）中和抗体以及TGF-β受体抑制剂SB 431542阻断。血管紧张素II处理的细胞培养液中TGF-β1的量增加，坎地沙坦或PD 123319抑制这种作用。血管紧张素II和TGF-β诱导的细胞迁移均被表皮生长因子（EGF）受体的中和抗体抑制，但不被EGF受体配体的中和抗体抑制。血管紧张素II诱导EGF受体磷酸化，坎地沙坦、PD 123319、SB 431542或β-arrestin 2耗竭可抑制该作用，但肝素结合EGF样生长因子的中和抗体不能抑制该作用。我们的研究结果表明，AT 1 R下游的β-抑制蛋白依赖性信号传导以及AT 2 R信号传导对于血管紧张素II诱导的角质形成细胞迁移是必需的，并且这种信号传导促进活性形式的TGF-β的产生，随后激活TGF-β受体，以及通过TGF-β受体反式激活EGF受体。
Re-epithelialization begins early during skin wound healing and is regulated by various growth factors and cytokines. Angiotensin II promotes the migration of keratinocytes and thereby contributes to wound healing. We investigated the mechanism by which angiotensin II stimulates human keratinocyte migration. Angiotensin II–induced keratinocyte migration was inhibited by an angiotensin II type 1 receptor (AT1R) antagonist (candesartan) or an angiotensin II type 2 receptor (AT2R) antagonist (PD123319) as well as by depletion of AT1R or AT2R. A biased agonist for AT1R, [Sar1,Ile4,Ile8]angiotensin II, induced cell migration, whereas depletion of β-arrestin2 inhibited angiotensin II–induced migration. Angiotensin II–induced migration was blocked by neutralizing antibodies to transforming growth factor-β (TGF-β) as well as by the TGF-β receptor inhibitor SB431542. The amount of TGF-β1 was increased in the culture medium of angiotensin II–treated cells, and this effect was inhibited by candesartan or PD123319. Both angiotensin II– and TGF-β–induced cell migration were inhibited by neutralizing antibodies to the epidermal growth factor (EGF) receptor but not by those to EGF receptor ligands. Angiotensin II–induced phosphorylation of the EGF receptor, and this effect was inhibited by candesartan, PD123319, SB431542, or depletion of β-arrestin2, but not by neutralizing antibodies to heparin-binding EGF-like growth factor. Our results indicate that β-arrestin–dependent signaling downstream of AT1R as well as AT2R signaling are necessary for angiotensin II–induced keratinocyte migration, and that such signaling promotes generation of the active form of TGF-β, consequent activation of the TGF-β receptor, and transactivation of the EGF receptor by the TGF-β receptor.