C-type natriuretic peptide modulates permeability of the blood-brain barrier
C-type natriuretic peptide modulates permeability of the blood-brain barrier
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DOI：
10.1038/jcbfm.2013.234
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发表时间：
2014-04-01
影响因子：
6.3
通讯作者：
Miyata, Atsuro
中科院分区：
文献类型：
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作者：
Bohara, Manoj;Kambe, Yuki;Miyata, Atsuro
C型利钠肽（CNP）在脑中含量丰富，有报道称其在血管细胞中发挥自分泌功能，但其对血脑屏障（BBB）通透性的影响尚不清楚。在这里，我们研究了这种影响。CNP（1、10和100 nmol/L）可剂量依赖性地显著降低由牛脑微血管内皮细胞和星形胶质细胞组成的体外BBB模型的跨内皮电阻（TEER）。C型利钠肽治疗降低了紧密连接（TJ）蛋白闭锁小带-1（ZO-1）的信使RNA（mRNA）和蛋白表达。ZO-1对TEER、mRNA和蛋白表达的影响可被cGMP类似物8-溴-cGMP（1 μ mol/L）模拟，并被蛋白激酶G（PKG）抑制剂Rp-8-CPT-cGMPS（100 μ mol/L）逆转，从而暗示PKG和cGMP信号在BBB功能中的作用。通过小干扰RNA敲低转录因子JunD不会导致CNP的渗透性改变。通过荧光素钠静脉给药（40 mg/kg）进行的小鼠脑荧光分析的体内研究也显示CNP（10 nmol/kg，静脉给药）显著增加了BBB通透性。这些发现表明CNP通过改变ZO-1表达来调节BBB通透性。
C-type natriuretic peptide (CNP) is abundant in brain and is reported to exert autocrine function in vascular cells, but its effect on blood brain barrier (BBB) permeability has not been clarified yet. Here, we examined this effect. Transendothelial electrical resistance (TEER) of in vitro BBB model, composed of bovine brain microvascular endothelial cells and astrocytes, was significantly dose dependently decreased by CNP (1, 10, and 100 nmol/L). C-type natriuretic peptide treatment reduced both the messenger RNA (mRNA) and protein expressions of tight junction (TJ) protein zonula occludens-1 (ZO-1). The effects on TEER, mRNA, and protein expressions of ZO-1 were mimicked by cyclic GMP (cGMP) analog 8-bromo-cGMP (1 mu mol/L) and reversed by protein kinase G (PKG) inhibitor Rp-8-CPT-cGMPS (100 mu mol/L), thus implying the role of PKG and cGMP signaling in BBB function. Transcription factor JunD knockdown by small interfering RNA resulted in no change of permeability by CNP. In vivo study of mouse brain by fluorimetric analysis with intravenous administration of sodium fluorescein (40 mg/kg) also showed a significant increase in BBB permeability by CNP (10 nmol/kg, intravenously). These findings suggest that CNP modulates the BBB permeability by altering ZO-1 expression.