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

Circ Res. 2007 Aug 3;101(3):268-76. doi: 10.1161/CIRCRESAHA.107.150474. Epub 2007 Jun 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / etiology
  • Albuminuria / prevention & control
  • Angiotensin II / toxicity
  • Animals
  • Atherosclerosis / physiopathology
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Gene Expression Regulation
  • Humans
  • Hypertension / complications*
  • Hypertension / metabolism
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / physiology
  • Inflammation / physiopathology
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • Kidney Diseases / etiology
  • Kidney Diseases / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Cardiovascular
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / physiology
  • NG-Nitroarginine Methyl Ester / toxicity
  • Nephritis / prevention & control
  • Nitric Oxide / physiology
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Organ Specificity
  • Receptor, TIE-1 / physiology
  • Recombinant Fusion Proteins / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Sodium Chloride, Dietary / toxicity
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Vascular Cell Adhesion Molecule-1 / biosynthesis
  • Vascular Cell Adhesion Molecule-1 / genetics

Substances

  • I-kappa B Proteins
  • Icam1 protein, mouse
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Recombinant Fusion Proteins
  • Sodium Chloride, Dietary
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Angiotensin II
  • Intercellular Adhesion Molecule-1
  • NF-KappaB Inhibitor alpha
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Receptor, TIE-1
  • NG-Nitroarginine Methyl Ester