In this study, we explored the mechanisms by which the angiotensin converting enzyme inhibitor (ACEI), enalapril, and the Ang II receptor blocker (ARB), losartan suppress oxidative stress and NF-κB activation-induced inflammatory responses in aged rat kidney. The experimentations were carried out utilizing aged (24-month-old) Brown Norway×Fischer 344 (F1) male rats which were randomized into 3 groups and administered enalapril (40mg/kg), losartan (30mg/kg) or placebo for 6months (daily p.o.). The level of reactive species (RS), peroxynitrite (ONOO-), GSH/GSSG and lipid peroxidation were measured. The activity of the pro-inflammatory transcription factor NF-κB, and gene expression of proteins in upstream signaling cascades were measured by electro-mobility shift assay (EMSA) and Western blotting. Enalapril and losartan differentially attenuated redox imbalance and the redox-sensitive transcription factor, the NF-κB pathway. Furthermore, stimulation of the NF-κB activation pathway by phosphorylation of p65 was attenuated by both compounds. Moreover, mediation of phosphorylation of p65 by phosphorylation of IκB kinase αβ (IKKαβ) and mitogen- and stress-activated protein kinase-1 (MSK-1), were also inhibited by enalapril and losartan. Finally, both compounds also lowered expression of NF-κB-dependent inflammatory genes, such as cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS). Only losartan lowered levels of 5-lipoxygenase (5-LOX). These findings indicate that enalapril and losartan differentially suppress inflammatory responses via inhibition of oxidative stress-induced NF-κB activation in aged rat kidney. © 2011 Elsevier Inc.