Role of NADPH oxidases (NOX) in the beneficial effects of dietary (-)-epicatechin on septic and metabolic kidney inflammation

PRINCE PD; FRAGA CG; GALLEANO M

Buenos Aires

Congreso; IV International Congress in Translational Medicine; 2018

Facultad de Farmacia y Bioquímica, UBA.

The anti-inflammatory effect of (‒)-epicatechin(EC) dietary supplementation was evaluated in two animal models with a pro-inflammatory component in the kidney: i) septic endotoxemia induced by acute lipopolysaccharide (LPS) administration, and ii) chronic fructose overload, that establishes a low-grade systemic inflammation, with increased levels of plasma LPS (metabolic endotoxemia).For the model of septic endotoxemia, male Sprague-Dawley rats were fed with chow diet with or without the EC supplementation (80 mg/kg BW). After 4 d, half of the animals receiving EC were administered sterile saline solution i.p. and the other half were administered LPS (4 mg/kg BW) i.p. for 6 h, obtaining the following experimental groups: control (CL); LPS (L); LPS-EC (LE). For the model of metabolic endotoxemia, male Sprague-Dawley rats received fructose 10% (p/v) in the drinking water for 8 w with or without the dietary supplementation of EC (20 mg/kg BW), obtaining the following experimental groups: control (CF); fructose (F); fructose-EC (FE). For both experimental designs, after euthanization the renal cortex was excised and processed for the western blot determinations.Fructose and LPS-treated rats showed an increase in superoxide anion production and increased expressions of NOX4 and p47phox, an activating subunit of NOX2 in renal cortex compared to their respective control groups (superoxide anion production: +107% F vs. CF, +107 L vs. CL; NOX4: +61% F vs. CF, +47% L vs. CL.; p47phox: +31% F vs. CF, +66% L vs. CL). Theses alterations were absent in the groups receiving EC (FE and LE groups). Both fructuose and LPS-treated groups F presented a pro-inflammatory profile in renal cortex compared to the control groups, with increased expressions of iNOS, TNFα and IL-6 and the activation of NF-κB signaling pathway, leading to an increased nuclear p65/cytosolic p65 content (F: +37% F vs. CF, +86% L vs. CL), that is an indicator of an increased translocation of NF-κB to the nucleus. EC dietary administration significantly decreased the expressions of these inflammatory molecules, the activation of NF-κB signaling pathway and the p65 nuclear/p65 cytosolic content. TLR-4 expression was increased in L group (+125% vs. CL and + 89% vs. LE), while no differences in this receptor expression was evidenced among CF, F and FE groups.These results suggest a potential role of NOX-derived reactive oxygen species contributing to the activation of NF-κB signaling pathway leading to an inflammatory state in the renal cortex of rat, in both models. The anti-inflammatory effect of EC could be attributed to the inhibition of NOX4 and p47phox expressions and the attenuation in the production of NOX-derived reactive oxygen species, thus attenuating fructose-overload or LPS-triggered inflammation mediated by NF-κB in kidney cortex of rat. Supported by PIP 11220170100585C (MG), UBACyT 20020160100132BA (CGF); the Packer-Wentz endowment 2017 (CGF).