Proinflammatory and antioxidant signaling pathways in kidney of high fat fed mice

E. CREMONINI; C. G. FRAGA; L. FISCHERMAN; M. GALLEANO; C. LITTERIO; P. I. OTEIZA

Kobe

Congreso; 9th International Conference on Polyphenols and Health; 2019

9th International Conference on Polyphenols and Health

Objectives: The aim of this study was to study the mechanisms involved in the prevention or attenuation of kidney inflammation and oxidative stress provided by dietary (-)-epicatechin (EC) on the alterations induced by high-fat diet consumption in mice. Materials and Methods: C57BL/6J male mice were fed for 14 w control (C) or high-fat diets (60% fat from lard), without (HF) or with 20 mg EC/kg body weight (HFE). At the end of the study, kidneys were isolated and the kidney cortex processed for IHC, to obtain total and nuclear fractions, and for mRNA isolation. Results: After 14 w on the high fat diet, body weight was higher in the HF and HFE mice (46.8 ±0.9 and 47.4 ±1.0 g, respectively) compared to both control groups (36.9 ±0.7 and 36.3 ±0.8 g, for C and CE groups respectively) . HF mice developed hyperglycemia and dyslipidemia, which were both mitigated by EC supplementation. High-fat fed mice showed increased kidney cortex vacuolization, compatible with an augmentation in lipid deposition, that was not affected by EC. Consumption of the high-fat diet led to endotoxemia, increased expression of kidney TLR4 receptor (73% over control values), MyD88 (62% over control values) (evaluated by Western blot), and AP-1-DNA binding measured by EMSA in nuclear fractions (78% over control values). EC supplementation prevented all these increases. The expression of TGFβ 1 was evaluated by IHC. Kidney cortex TGFβ 1 levels in HF mice were 15-fold higher than in C mice, while only a 5-fold increase over the C group was observed in the EC-supplemented mice. The activation of NF-κB and HIF-1 (measured as their DNA-binding activity in nuclear fractions) was not affected by high-fat diet consumption. In terms of antioxidant defenses, the Nrf2 pathway was not affected in HF mice, as evidenced by both EMSA assays and by the unaffected expression of Nrf2-dependent genes, i.e. glutamate-cysteine ligase modulatory and catalytic subunits, and peroxirredoxin 1. Conclusions: In a model of high fat diet-induced obesity mice developed kidney inflammation with evidence of fibrosis, which were both mitigated by EC. Inflammation was suggested by an increased expression of TLR4, accompanied by the activation of the MyD88/AP-1 pathway, which was not observed when mice were supplemented with dietary EC. In summary, dietary EC can protect the kidneys from the inflammatory damage associated with consumption of high fat diets and obesity.