Tumor necrosis factor-alpha (TNF-) has been implicated in the pathogenesis of hypertension and renal injury. However, the direct effects of TNF- on renal hemodynamic and excretory function are not yet clearly defined. We examined the renal responses to infusion of TNF- (0.33 ng/g/min) in anesthetized mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and Inulin clearance. The urine was collected from a cannula inserted into the bladder. Following the 60 min control clearance period, TNF- infusion was initiated and 15 min were given for stabilization followed by another 60 min clearance period. TNF- alone (n=7) caused decreases in RBF (7.9±0.3 to 6.4±0.3 mL/min/g) and GFR (1.04±0.06 to 0.62±0.08 mL/min/g) as well as increases in absolute (0.8±0.3 to 1.4±0.3 mmol/min/g) and fractional excretion of sodium (0.5±0.2 to1.5±0.4%) without affecting arterial pressure. TNF- also increased 8-isoprostane excretion (8.10±1.09 to 11.13±1.34 pg/min/g). Pre-treatment with TNF- blocker, etanercept (5 mg/kg, s.c; 24 & 3 hr before TNF- infusion; n=6) abolished these responses. However, TNF- induced an increase in RBF and caused attenuation of the GFR reduction in mice pre-treated with superoxide (O₂^-) scavenger, tempol (2µg/gm/min; n=6). Pre-treatment with nitric oxide (NO) synthase inhibitor, L-NAME (0.1µg/gm/min; n=6) resulted in further enhancement in vasoconstriction while natriuresis remained unaffected in response to TNF-. These data suggest that TNF- induces renal vasoconstriction and hypofiltration via enhancing the activity of O₂^- and thus, reducing the activity of NO. The natriuretic response to TNF- is related to its direct effects on tubular sodium reabsorption.