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.