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

Tumor necrosis factor-α (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_TNF-αV) 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 ip once daily for 3 days before the experiment day; n = 7) treated mice. TNF-α concentration in samples was determined using an enzyme-linked immunosorbent assay (ELISA) kit (Bioscience, Woburn, MA). During baseline period, TNF-α level in plasma was undetected, but it increased during the 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_TNF-αV 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_TNF-αV (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.NEW & NOTEWORTHY These findings demonstrate for the first time that enhanced rate infusion of saline resulted in TNF-α production that exerts a natriuretic response, which strongly suggests a "physiological" role for this well-known proinflammatory cytokine in regulating renal function during acute salt loading. These results may confer therapeutic implications with predominant use of saline in patients with inflammatory conditions that are associated with significantly greater morbidity and mortality than those with predominant use of other balanced fluids.