title: Vascular endothelial cell-specific NF-kappaB suppression attenuates hypertension-induced renal damage.
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.
authors.affiliation: Medical Faculty of the Charité, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Henke
authors.forename: Ruth
authors.initials: R
authors.lastname: Schmidt-Ullrich
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: Maren
authors.initials: M
authors.lastname: Wellner
authors.forename: Michael
authors.initials: M
authors.lastname: Obst
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gross
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Claus
authors.initials: C
authors.lastname: Scheidereit
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000517:prevention & control; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D050197:Atherosclerosis / Q000503:physiopathology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D009393:Nephritis / Q000517:prevention & control; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D009928:Organ Specificity; D042810:Receptor, TIE-1 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020672:I-kappa B Proteins; C090509:Icam1 protein, mouse; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011993:Recombinant Fusion Proteins; D017673:Sodium Chloride, Dietary; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D042810:Receptor, TIE-1; D019331:NG-Nitroarginine Methyl Ester