Aspirin Inhibits Renal I-κB Kinase Activity, Nf-κB and Protects Against Renal and Cardiac Damage in Rats with Human Renin and Angiotensinogen Genes (dTGR)

Abstract

P4 In a recent report, aspirin (ASA) inhibited I-κB kinase beta in vitro; however, in vivo relevance has not been shown. We previously showed that NF-κB activation and inflammation are crucial role in the pathogenesis of Ang II-induced vasculopathy. We now tested the hypothesis that ASA inhibits NF-κB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, renal and cardiac damage and die at 7 weeks. We treated rats chronically with ASA (600 and 25 mg/kg/d ip). Only ASA 600 prevented mortality, while untreated dTGR and ASA 25 showed mortality >50% at 7 weeks. ASA 600 reduced cardiac hypertrophy (4.0±0.2 vs. 5.7±0.2 mg/g, p<0.001) compared to dTGR. Blood pressure levels in ASA 600 were slightly, but not significantly lower (158±8 vs. 182±8 mm Hg, p=0.2). In contrast, ASA 600 reduced albuminuria by 85 % (p<0.01) and perivascular fibrosis, while ASA 25 had no effect on cardiac and renal damage. ASA 600 inhibited renal I-κB kinase activity and NF-κB DNA binding activity, which were increased in dTGR. Immunostaing of the activated p65 NF-κB subunit was increased in the endothelium, smooth muscles cells, infiltrated cells, glomeruli, and tubules of dTGR and markedly reduced by ASA 600. ASA 600 also reduced immunostaining of NF-κB-regulated genes laminin, ICAM-1, and IL-6. Monocyte infiltration was increased in dTGR hearts and kidneys and reduced by ASA 600, and not by ASA 25. These results demonstrate that high-dose ASA inhibits NF-κB, suppresses inflammation, and protects against ANG II-induced end-organ damage. The data underscore the role of inflammation and identify a novel drug target in this model.