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

TLDR

NF‑κB contributes to vascular and target‑organ injury in hypertension. The study aimed to determine whether endothelial‑cell‑specific NF‑κB inhibition could mitigate hypertension‑induced damage. They created Tie‑1‑ΔN transgenic mice expressing an endothelial‑restricted NF‑κB super‑repressor, confirmed its activity, and induced hypertension with high‑salt, L‑NAME, and Ang II. Despite similar blood‑pressure elevations, Tie‑1‑ΔN mice exhibited less renal injury, inflammation, albuminuria, and lower VCAM‑1/ICAM‑1 expression, demonstrating that endothelial NF‑κB activation drives hypertension‑induced renal damage and its suppression protects the kidney.

Abstract

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