Vascular Endothelial Cell–Specific NF-&kgr;B Suppression Attenuates Hypertension-Induced Renal Damage

Nuclear factor kappa B (NF-&kgr;B) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell–specific NF-&kgr;B suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell–restricted NF-&kgr;B super-repressor I&kgr;B&agr;&Dgr;N (Tie-1-&Dgr;N mice) overexpression. We confirmed cell-specific I&kgr;B&agr;&Dgr;N expression and reduced NF-&kgr;B activity after TNF-&agr; stimulation in primary endothelial cell culture. To induce hypertension with target-organ damage, we fed mice a high-salt diet and N(omega)-nitro-l-arginine-methyl-ester (L-NAME) and infused angiotensin (Ang) II. This treatment caused a 40-mm Hg blood pressure increase in both Tie-1-&Dgr;N and control mice. In contrast to control mice, Tie-1-&Dgr;N mice developed a milder renal injury, reduced inflammation, and less albuminuria. RT-PCR showed significantly reduced expression of the NF-&kgr;B targets VCAM-1 and ICAM-1, compared with control mice. Thus, the data demonstrate a causal link between endothelial NF-&kgr;B activation and hypertension-induced renal damage. We conclude that in vivo NF-&kgr;B suppression in endothelial cells stops a signaling cascade leading to reduced hypertension-induced renal damage despite high blood pressure.

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