NF-kappa B inhibition ameliorates angiotensin II-induced inflammatory damage in rats

We recently reported that the activation of nuclear factor-kappa B (NF-kapp a B) promotes inflammation in rats harboring both human renin and angiotens inogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-kappa B and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Elec trophoretic mobility shift assay showed increased NF-kappa B DNA binding ac tivity 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 co mpared with dTGR controls. The cardiac hypertrophy index was also significa ntly 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 pr evented death. Vascular injury was ameliorated in small renal;md cardiac ve ssels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-k appa B binding activity in heart and kidney, whereas AP-1 activity in the k idney was not decreased. dTGR exhibited increased left ventricular c-fos an d c-jun mRNA expression. PDTC treatment reduced c-fos but not c-jun mRNA. I mmunohistochemistry showed increased p65 NF-kappa B subunit expression in t he endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PD TC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF -kappa B-dependent transactivation of the intercellular adhesion molecule I CAM-1 and inducible nitric oxide synthase. Monocyte infiltration was marked ly increased in dTGR kidneys and hearts. Chronic treatment reduced naonacyt e/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-kappa B activity, ameliorates inflammati on, and protects against angiotensin II-induced end-organ damage.