NATRIURESIS INDUCED BY ACUTE INTRAVENOUS SALINE INFUSION IN MICE IS MEDIATED BY TUMOR NECROSIS FACTOR-ALPHA (TNF) - EVIDENCE FOR PHYSIOLOGICAL ROLE OF THIS CYTOKINE IN KIDNEY

Abstract

Objective: Chronic high salt (HS) intake in diet is associated with exacerbation of inflammation as well as hypertension. HS intake, through ‘osmoreceptor function’, induces an immune mechanism that activates the mononuclear phagocyte system (MPS) cells in the myeloid tissues which then circulated and infiltrated in many organs including the kidney. These infiltrated MPS cells release TNF that appears in the circulation in its soluble form (sTNF). We hypothesize that the intravenous saline infusion can also induce the production of sTNF from MPS cells due to an increase in salt content in immune tissues and this sTNF influences saline induced natriuretic response in the kidney. Design and method: To examine this hypothesis, we measured the changes in sTNF levels in plasma and urinary excretion rate (UTNFV) 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; saline volume infusion period) in anesthetized mice (n = 5). The concentration of sTNF in plasma and urine samples were determined using ELISA kit (Ebioscience, Woburn, MA) for measuring this cytokine. Results: Baseline level of plasma sTNF was undetectable, however, the level was increased to 3.7±1.3 pg/mL during saline volume infusion period. Baseline UTNFV level was 0.01±0.002 pg/min/g of kidney wt, which was increased to 0.11±0.03 pg/min/g (P<0.05) during volume infusion period. In another group of mice (n = 5) pretreated with a TNF inhibitor, etanercept (0.5 mg/kg intraperitoneally once daily for 3 days prior to the experiment day), it was observed that this increase in UTNFV during saline volume infusion period was markedly attenuated (0.003±0.002 to 0.006±0.004 pg/min/g; P = n.s.). The usual natriuretic response (0.5±0.2 to 3.8 ±1.1 μmol/min/g; P<0.05) to saline volume infusion observed in control mice was seen markedly attenuated (0.4±0.1 to 0.8±0.3 μmol/min/g; P = n.s.) in etanercept pretreated mice. Conclusions: These findings demonstrate for the first time that an intravenous saline volume infusion resulted an increase in sTNF level in plasma and in urine. These results strongly suggest a physiological role for sTNF in regulating renal excretory function during saline volume expansion.