Abstract P147: Attenuation Of Diuretic And Natriuretic Responses To Acute Saline Volume Expansion In Mice Pre-treated With Tumor Necrosis Factor-alpha (TNFα) Inhibitor, Etanercept.

Abstract

Listen

Translate article

High salt intake induces an immune response that activates the mononuclear phagocyte system (MPS) cells to produce TNFα. We have previously demonstrated that intravenous infusion of TNFα in mice induces diuresis and natriuresis by inhibiting renal tubular sodium reabsorption. We hypothesize that the intravenous saline infusion can also induce the production of TNFα from MPS cells and such increase in TNFα influences saline induced natriuresis in the kidney. To examine this hypothesis, we measured the changes in TNFα levels in plasma and in urinary excretion rate (U TNFα V) during intravenous infusion of isotonic saline (0.9% NaCl), first at euvolemic condition (3 μL/min for 60 min; Baseline period) and then at an enhanced infusion rate (12 μL/min for 90 min; Volume expansion period) in anesthetized mice (n=5). Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by PAH and inulin clearances respectively. TNFα concentration in plasma and urine samples were determined using ELISA kit (Ebioscience, Woburn, MA). TNFα level in plasma collected during baseline period was undetectable, however, TNFα was increased to 3.7±1.3 pg/mL during volume expansion (VE) period. Baseline U TNFα V level was 0.01±0.002 pg/min/g (kidney wt), which was increased to 0.11±0.03 pg/min/g (P<0.05) during VE period. VE increased urine flow (V, 5.4±0.5 to 22.0±5.1 μL/min/g; P<0.05) and sodium excretion (U Na V; 0.54±0.19 to 4.84 ±1.16 μmol/min/g; P<0.05) without significant changes in RBF (7.1±1.0 to 6.0±1.8 mL/min/g) and GFR (1.18±0.11 to 0.94±0.28 mL/min/g). Interestingly, the diuretic and natriuretic responses to VE were markedly attenuated in mice (n=5) pretreated with a TNFα inhibitor, etanercept (ETN; 0.5 mg/kg intraperitoneally once daily for 3 days prior to the experiment day). VE induced changes in ETN treated mice are as follows: V, 5.9±0.65 to 7.9 ±1.6 μL/min/g; U Na V, 0.43±0.6 to 1.1±0.28 μmol/min/g; RBF, 5.4±0.4 to 6.6±0.9 mL/min/g and GFR, 0.87±0.09 to 0.98±0.13 mL/min/g. These findings demonstrate for the first time that an intravenous saline volume infusion resulted an increase in TNFα level in plasma and in urine. These results strongly suggest a physiological role for TNFα in regulating renal excretory function during saline volume expansion.