Vascular endothelial cell-specific NF-κB suppression attenuates hypertension-induced renal damage

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.