RENAL VASOCONSTRICTION AND NATRIURESIS INDUCED BY TUMOR NECROSIS FACTOR (TNF)‐α ARE MEDIATED BY TNF RECEPTOR TYPE 1

Abstract

Infusion of TNF‐α exerts renal vasoconstriction as well as natriuresis in mice. To define the receptor subtypes involved in these renal vascular and tubular actions of TNF‐α, experiments were conducted to assess the responses to human recombinant TNF‐α (0.33ng/min/g BW; i.v. infusion for 75 min) in gene knockout mice for either TNF receptor type 1 (TNFR1KO; n=6) or type 2 (TNFR2KO; n=6) and compared these results with those obtained in corresponding wild type (WT; C57BL6; n=6) mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearances respectively. As reported previously, TNF‐α infusion in WT mice resulted in decreases of 20±5% (P<0.03) in RBF, 40±2% (P<0.003) in GFR as well as increases in 83±27% (0.05>P>0.01) in urine flow (V) and 363±104% (P<0.05) in sodium excretion (UNaV). These responses are completely absent in TNFR1KO mice. TNF‐α infusion in TNFR1KO mice resulted in non‐significant changes in renal parameters (RBF; 8±22%; GFR, −18±14%; V, 15±16%; UNaV, −47±12%). However, TNF‐α infusion in TNFR2KO mice showed similar changes in renal parameters as observed those in the WT mice. The responses in TNFR2KO mice are as follows: RBF; −22±10 % (0.05>P>0.01); GFR, −36±7% (P<0.002); V, 91±19% (P<0.007); UNaV, 327±70% (P<0.01). These data demonstrate that TNF receptor type 1, not the type 2, is involved in mediating acute renal vascular and tubular actions of TNF‐α.