African Americans have a fourfold greater likelihood of developing end-stage renal disease (ESRD) compared with Caucasians. It has been proposed that the increased prevalence may be explained by non-traditional factors such as environmental stress and psychosocial factors. In this study, we used infrequent running to exhaustion as a physiological stressor to mimic real life experiences, such walking up stairs when an elevator is malfunctioning or running to catch a bus, to study its effect on renal injury in a hypertensive mouse model (endothelial nitric oxide synthase-deficient mice; eNOS(-/-)). This model has previously been shown to have renal injury comparable to that observed in African Americans. The effect of physiological stress on renal injury was examined in the setting of low (0.12%), control (0.45%) and high (8%) dietary salt. Following bouts of physiological stress, eNOS(-/-) mice had significantly greater interstitial inflammation compared with unstressed eNOS(-/-) mice (two-way analysis of variance (2-ANOVA), Holm-Sidak; P<0.01). Interestingly, eNOS(-/-) mice on a high-salt diet had greater interstitial inflammation compared with similarly stressed eNOS(-/-) mice on a low- or control-salt diet (2-ANOVA, Holm-Sidak; P<0.03). These effects of stress were independent of systolic blood pressure (141±7, 143±4, and 158±8 vs. 141±4, 138±5, 150±4 mm Hg; end of study vs. baseline, respectively). There was no significant effect of stress or dietary salt on renal injury in control wild-type mice (eNOS(+)/(+)). These data demonstrate that physiological stress exacerbates the renal injury associated with hypertension and that high-salt compounds this effect of stress. These results provide support for the idea that psychosocial and environmental factors contribute to the increased prevalence of ESRD in hypertensive African Americans.