Vascular endothelial cell-specific NF-κB suppression attenuates hypertension-induced renal damage
Vascular endothelial cell-specific NF-κB suppression attenuates hypertension-induced renal damage
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DOI：
10.1161/circresaha.107.150474
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发表时间：
2007-08-03
影响因子：
20.1
通讯作者：
Muller, Dominik N.
中科院分区：
文献类型：
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作者：
Henke, Norbert;Schmidt-Ullrich, Ruth;Muller, Dominik N.
核因子-κ B（NF-κ B）参与高血压引起的血管和靶器官损伤。我们测试了内皮细胞特异性NF-κ B抑制是否会改善。我们用内皮细胞限制性NF-κ B超阻遏物I κ B alpha Delta N（Tie-1-Delta N小鼠）过表达产生Cre/lox转基因小鼠。我们证实了在原代内皮细胞培养物中TNF-α刺激后细胞特异性I κ B α Δ N表达和NF-κ B活性降低。为了诱导高血压伴靶器官损伤，我们给小鼠喂高盐饮食和N（ω）-硝基-精氨酸甲酯（L-NAME），并输注血管紧张素（Ang）II。这种治疗导致Tie-1-Delta N和对照小鼠的血压升高40 mm Hg。与对照小鼠相比，Tie-1-Delta N小鼠的肾损伤更轻，炎症减少，白蛋白尿减少。RT-PCR显示与对照小鼠相比，NF-κ B B靶点VCAM-1和ICAM-1的表达显著降低。因此，这些数据证明了内皮NF-κ B B活化和高血压诱导的肾损伤之间的因果关系。我们的结论是，在体内NF-κ B B抑制内皮细胞停止信号级联导致减少高血压引起的肾损害，尽管高血压。
Nuclear factor kappa B (NF-kappa B) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell-specific NF-kappa B suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell-restricted NF-kappa B super-repressor I kappa B alpha Delta N (Tie-1-Delta N mice) overexpression. We confirmed cell-specific I kappa B alpha Delta N expression and reduced NF-kappa B activity after TNF-alpha stimulation in primary endothelial cell culture. To induce hypertension with target-organ damage, we fed mice a high-salt diet and N(omega)-nitro-Largininemethyl-ester (L-NAME) and infused angiotensin (Ang) II. This treatment caused a 40-mm Hg blood pressure increase in both Tie-1-Delta N and control mice. In contrast to control mice, Tie-1-Delta N mice developed a milder renal injury, reduced inflammation, and less albuminuria. RT-PCR showed significantly reduced expression of the NF-kappa B targets VCAM-1 and ICAM-1, compared with control mice. Thus, the data demonstrate a causal link between endothelial NF-kappa B activation and hypertension-induced renal damage. We conclude that in vivo NF-kappa B suppression in endothelial cells stops a signaling cascade leading to reduced hypertension-induced renal damage despite high blood pressure.