Vascular Endothelial Cell–Specific NF-κB Suppression Attenuates Hypertension-Induced Renal Damage

Abstract

Nuclear factor kappa B (NF-κB) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell–specific NF-κB suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell–restricted NF-κB super-repressor IκBαΔN (Tie-1-ΔN mice) overexpression. We confirmed cell-specific IκBαΔN expression and reduced NF-κB activity after TNF-α 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-ΔN and control mice. In contrast to control mice, Tie-1-ΔN mice developed a milder renal injury, reduced inflammation, and less albuminuria. RT-PCR showed significantly reduced expression of the NF-κB targets VCAM-1 and ICAM-1, compared with control mice. Thus, the data demonstrate a causal link between endothelial NF-κB activation and hypertension-induced renal damage. We conclude that in vivo NF-κB suppression in endothelial cells stops a signaling cascade leading to reduced hypertension-induced renal damage despite high blood pressure.