Renal vasoconstrictor and natriuretic effects of acute administration of human recombinant TNF‐α (rTNFα) in mice

Abstract

Previous studies have implicated a role for TNFα in the pathogenesis of renal injury in hypertension and other chronic conditions. TNFα has also been shown to inhibit ENaC activity in many in‐vitro studies. However, the acute effects of TNFα on renal function in‐vivo are not yet clearly defined. We examined the renal responses to continuous infusion of rTNFα (0.33 μg/kg/min) in anesthetized mice (C57BL/6). Arterial pressure (AP) was recorded from a carotid arterial cannula. Urine was collected from a cannula inserted into the bladder. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearance. Following the consecutive two 30 min control urine collections, rTNFα infusion was initiated. After 15 min of stabilization, another two 30 min collections were made. rTNFα (n=6) 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) without altering AP. However, there were increases in urine flow (9.3±1.4 to 15.0±2.0 μl/min/g) and sodium excretion (0.8±0.3 to 1.4±0.3 μmol/min/g). These responses were not seen in animals pretreated with a TNFα blocker, etanercept (5 mg/kg, ip; 24 hr before rTNFα; n=5). Pretreatment with tempol (2μg/gm/min; i.v. started 2 hr before rTNFα; n=4) also attenuated the decreases in RBF and GFR but the renal excretory responses to rTNFα remained unaffected. These data suggest that superoxide production mediates the renal vasoconstrictor effect of TNFα while the natriuretic effect may be due to its inhibitory action on ENaC. Supported by grant RO1HL‐066432.