African Americans have an increased incidence of end-stage renal disease and are characterized as having reduced bioavailability of nitric oxide and salt-sensitivity. We propose that endothelial nitric oxide synthase (eNOS) knockout mice (eNOS(-/-)) are a suitable model of hypertension-associated renal injury as seen in African Americans. Therefore, the purpose of this study was to determine whether older eNOS(-/-) mice have hypertension-associated renal injury and if dietary salt modulates this injury. Six-month-old eNOS(-/-) mice were placed on 0.12%, 0.45% or 8% NaCl diet for 8 weeks and blood pressure measured weekly; kidneys were collected for pathology evaluation and scoring at the end of the 8-week period. Mice deficient of eNOS were hypertensive at baseline compared with control mice in all three groups (128+/-3 vs. 112+/-3, P<0.05). Blood pressure was significantly elevated from baseline in eNOS(-/-) on 0.45 and 8% salt diets (P<0.02). The composite renal pathology scores for eNOS(-/-) mice were significantly greater than wild-type mice, indicating high salt intake exacerbates the injury (P<0.001 vs. normal salt diet). eNOS(-/-) mice may be used as a model of salt-induced and hypertension-associated renal injury as seen in African Americans.