Studies suggest that the inflammatory cytokine, TNF, plays a role in the prognosis of end-stage renal disease. We hypothesized that TNF contributes to renal inflammation in a model of mineralocorticoid-induced hypertension. Four groups of rats (n=5-6) were studied for 3 weeks with the following treatments 1) placebo, 2) placebo + TNF inhibitor, etanercept (1.25 mg/kg/day, sc), 3) deoxycorticosterone acetate plus 0.9 % NaCl to drink (DOCA-salt), or 4) DOCA-salt + etanercept. Mean arterial blood pressure (MAP) measured by telemetry increased in DOCA-salt rats compared to baseline (177±4 vs. 107±3 mmHg, P<0.05) and TNF inhibition had no effect in the elevation of MAP in these rats (177±8 mmHg). Urinary protein excretion significantly increased in DOCA-salt rats compared to placebo (703±76 vs. 198±5 mg/day, respectively); etanercept lowered the proteinuria (514±64 mg/day, P<0.05 vs. DOCA-salt alone). Urinary albumin excretion followed a similar pattern in each group. Urinary MCP-1 and ET-1 excretion were also increased in DOCA-salt rats compared to placebo (MCP-1: 939±104 vs. 43±7 ng/day, and ET-1: 3.30±0.29 vs. 1.07±0.03 fmol/day, respectively, both P<0.05); TNF inhibition significantly decreased both MCP-1 and ET-1 excretion (409±138 ng/day and 2.42±0.22 fmol/day, respectively, both P<0.05 vs. DOCA-salt alone). Renal cortical expression of ICAM-1, NFKB, TGF, and TNF mRNA increased in DOCA-salt rats and etanercept reduced these changes. Renal cortical NFKB activity also increased in DOCA-salt hypertensive rats and etanercept treatment significantly reduced this effect. These data support the hypothesis that TNF contributes to the increase in renal inflammation in DOCA-salt rats.