title: NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats.
abstract: We recently reported that the activation of nuclear factor-kappaB (NF-kappaB) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-kappaB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility shift assay showed increased NF-kappaB DNA binding activity in hearts and kidneys of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162+/-8 versus 190+/-7 mm Hg; P=0.02) in dTGR compared with dTGR controls. The cardiac hypertrophy index was also significantly reduced (4.90+/-0.1 versus 5.77+/-0.1 mg/g; P<0. 001). PDTC reduced 24-hour albuminuria by >95% (2.5+/-0.8 versus 57. 1+/-8.7 mg/d; P<0.001) and prevented death. Vascular injury was ameliorated in small renal and cardiac vessels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-kappaB binding activity in heart and kidney, whereas AP-1 activity in the kidney was not decreased. dTGR exhibited increased left ventricular c-fos and c-jun mRNA expression. PDTC treatment reduced c-fos but not c-jun mRNA. Immunohistochemistry showed increased p65 NF-kappaB subunit expression in the endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF-kappaB-dependent transactivation of the intercellular adhesion molecule ICAM-1 and inducible nitric oxide synthase. Monocyte infiltration was markedly increased in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-kappaB activity, ameliorates inflammation, and protects against angiotensin II-induced end-organ damage.
authors.affiliation: Franz Volhard Clinic, Medical Faculty of the Charité, Berlin, German.
authors.forename: D N
authors.initials: DN
authors.lastname: Muller
authors.forename: R
authors.initials: R
authors.lastname: Dechend
authors.forename: E M
authors.initials: EM
authors.lastname: Mervaala
authors.forename: J K
authors.initials: JK
authors.lastname: Park
authors.forename: F
authors.initials: F
authors.lastname: Schmidt
authors.forename: A
authors.initials: A
authors.lastname: Fiebeler
authors.forename: J
authors.initials: J
authors.lastname: Theuer
authors.forename: V
authors.initials: V
authors.lastname: Breu
authors.forename: D
authors.initials: D
authors.lastname: Ganten
authors.forename: H
authors.initials: H
authors.lastname: Haller
authors.forename: F C
authors.initials: FC
authors.lastname: Luft
mesh_terms: D000804:Angiotensin II / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics; D003326:Coronary Circulation; D003327:Coronary Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004247:DNA / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007674:Kidney Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D012083:Renin / Q000235:genetics; D013859:Thiocarbamates / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics; D014657:Vasculitis / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology
chemical_list: D000975:Antioxidants; D018932:Chemokine CCL2; D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; C020972:pyrrolidine dithiocarbamic acid; D004247:DNA; D019001:Nitric Oxide Synthase; D012083:Renin