Although many studies have indicated that fish oil (FO) improves cardiovascular risk factors and reduces histopathologic manifestations of injury in experimental renal injury models, potential mechanisms underlying this protective effect have not been adequately defined. The objective of this study was to identify potential signaling pathways that confer protection in the Dahl rat model of salt-sensitive hypertension. Male Dahl salt-sensitive rats (n=10 per group) were provided with formulated diets containing 8% NaCl, 20% protein, and 25% FO or 25% corn oil (CO) for 28 days. FO reduced blood pressure (-11% at 4 weeks, P<0.05), urine protein excretion (-45% at 4 weeks, P<0.05), plasma cholesterol and triglyceride levels (-54%, P<0.001 and -58%, P<0.05), and histopathologic manifestations of renal injury, including vascular hypertrophy, segmental and global glomerular sclerosis, interstitial fibrosis, and tubular atrophy. Interstitial inflammation was significantly reduced by FO (-32%, P<0.001), as assessed by quantitative analysis of ED1-positive cells in sections of renal cortex. FO reduced tubulointerstitial proliferative activity, as assessed by Western blot analysis of cortical homogenates for PCNA (-51%, P<0.01) and quantitative analysis of Mib-1 stained sections of renal cortex (-42%, P<0.001). Decreased proliferative activity was associated with reduced p-ERK expression (-37%, P<0.005) and NF-B activation (-42%, P<0.05). FO reduced COX-2 expression (-63%, P<0.01) and membrane translocation of the NADPH oxidase subunits p47phox and p67phox (-26% and -34%, P<0.05). We propose that FO ameliorates renal injury in Dahl salt-sensitive rats through inhibition of ERK, decreased NF-B activation, inhibition of COX-2 expression, and decreased NADPH oxidase activation.