Tumor necrosis factor-alpha in mediation of acute salt loading induced natriuresis in mice; evidence for its physiological role in regulating kidney function.

Abstract

Tumor necrosis factor-alpha (TNF-α) exerts natriuresis via activation of its receptor type 1 in the kidney. Although chronic high salt (HS) intake produces this cytokine by immune activation of the mononuclear phagocyte cells, it has not yet been examined whether acute salt loading produces this cytokine and can induce consequent natriuresis. Here, we measured the changes in plasma level and urinary excretion rate of TNF-α (U_TNFαV) during intravenous infusion of isotonic saline (0.9% NaCl), first at euvolemic conditions (3 µL/min for 60 min; Baseline period) and then at an enhanced infusion rate (12 µL/min for 90 min; Salt-loading period) in control mice (n=7) and TNF-α inactivator, etanercept (ETN; 0.5 mg/kg intraperitoneally once daily for 3 days prior to the experiment day; n=7) treated mice. TNF-α concentration in samples were determined using ELISA kit (Bioscience, Woburn, MA). During Baseline period, TNF-α level in plasma was undetected but it increased during salt-loading period in both control (3.7±1.3 pg/mL) and ETN treated (3.3±1.2 pg/mL) mice. In control mice, the baseline U_TNFαV was minimal (0.01±0.002 pg/min/g) but increased to 0.1±0.03 pg/min/g (P<0.05) with associated increase in urinary sodium excretion (U_NaV; 0.5±0.2 to 4.8 ±1.2 µmol/min/g; P<0.05) during salt-loading period. In ETN treated mice, both the U_TNFαV (0.01±0.004 to 0.02±0.01 pg/min/g) and U_NaV (0.4±0.6 to 1.1±0.3 µmol/min/g) responses to salt-loading were markedly attenuated. These findings demonstrate that TNF-α contributes to saline induced natriuresis, suggesting a physiological role for this cytokine in regulating renal excretory function during acute salt loading.