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

¹Department of Physiology, Tulane University Health Sciences Center, New Orleans; and ²Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana

Submitted 7 May 2008 ; accepted in final form 8 October 2008

Tumor necrosis factor- (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^–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- 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^–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- also increased 8-isoprostane excretion (8.10 ± 1.09 to 11.13 ± 1.34 pg·min^–1·g^–1). Pretreatment with TNF- blocker etanercept (5 mg/kg sc; 24 and 3 h before TNF- infusion; n = 6) abolished these responses. However, TNF- induced an increase in RBF and caused attenuation of the GFR reduction in mice pretreated with superoxide (O₂^–) 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-. 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.

superoxide; nitric oxide; renal hemodynamic; sodium excretion

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