Tumor necrosis factor-α induces renal vasoconstriction as well as natriuresis in mice

Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of hypertension and renal injury. However, the direct effects of TNF-α on renal hemodynamic and excretory function are not yet clearly defined. We examined the renal responses to infusion of TNF-α (0.33 ng·g(−1)·min(−1)) 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-α infusion was initiated and 15 min were given for stabilization followed by another 60-min clearance period. TNF-α alone (n = 7) caused decreases in RBF (7.9 ± 0.3 to 6.4 ± 0.3 ml·min(−1)·g(−1)) and GFR (1.04 ± 0.06 to 0.62 ± 0.08 ml·min(−1)·g(−1)) as well as increases in absolute (0.8 ± 0.3 to 1.4 ± 0.3 μmol·min(−1)·g(−1)) and fractional excretion of sodium (0.5 ± 0.2 to 1.5 ± 0.4%) without affecting arterial pressure. TNF-α also increased 8-isoprostane excretion (8.10 ± 1.09 to 11.13 ± 1.34 pg·min(−1)·g(−1)). Pretreatment with TNF-α blocker etanercept (5 mg/kg sc; 24 and 3 h before TNF-α infusion; n = 6) abolished these responses. However, TNF-α induced an increase in RBF and caused attenuation of the GFR reduction in mice pretreated with superoxide (O(2)(−)) scavenger tempol (2 μg·g(−1)·min(−1); n = 6). Pretreatment with nitric oxide (NO) synthase inhibitor nitro-l-arginine methyl ester (0.1 μg·g(−1)·min(−1); n = 6) resulted in further enhancement in vasoconstriction while natriuresis remained unaffected in response to TNF-α. These data suggest that TNF-α induces renal vasoconstriction and hypofiltration via enhancing the activity of O(2)(−) and thus reducing the activity of NO. The natriuretic response to TNF-α is related to its direct effects on tubular sodium reabsorption.