Dexamethasone Inhibits Nf-κB, P22phox, and Protects Against Angiotensin Ii-Induced Renal Damage
We recently reported that NF-κB activation promotes inflammation in rats harboring both human renin and angiotensinogen genes (dTGR). We now tested the hypothesis that dexamethasone (DEX) inhibits NF-κB and ameliorates renal and cardiac end-organ damage. The dTGR feature moderate hypertension, severe renal, and cardiac damage, as well as over 50% mortality at 7 weeks. Immunohistochemical analysis shows increased infiltration of monocytes and T-cells. Electrophoretic mobility shift assay showed increased NF-κB DNA binding activity in heart and kidney of dTGR. One-week treatment with DEX (1 mg/kg/d i.p.) initially increased blood pressure at week 5, compared to dTGR (191±2 vs.152±6 mm Hg, p<0.01), whereas blood pressure was not different at week 7 (193±15 vs. 182±8 mm Hg, p=0.8). However, DEX reduced 24 h albuminuria by 85 % (2.7±0.5 vs. 18.0±3.4 mg/d, p<0.001) and prevented mortality completely. Vasculopathy was ameliorated in kidney and heart and perivascular fibrosis was reduced. DEX inhibited NF-κB DNA-binding activity and also the NF-κB-regulated adhesion molecule ICAM-1. We also studied localization of NADPH subunit p22phox. Immunostaining of p22phox was detected in the endothelium and also colocalized with monocytes. DEX reduced both infiltration of cells and p22phox expression. Thus, these results demonstrate that DEX suppresses NF-κB binding activity, p22phox expression of infiltrated cells, inflammation, and protects against angiotensin II-induced end-organ damage, all without blood pressure reduction.