Milena B Stockler-Pinto1,2, Christophe O Soulage3, Natália A Borges4, Ludmila F M F Cardozo4, Carla J Dolenga5, Lia S Nakao5, Roberto Pecoits-Filho6, Denis Fouque7, Denise Mafra4,8. 1. Graduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil. milbarcza@gmail.com. 2. Graduate Program in Nutrition Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil. milbarcza@gmail.com. 3. Univ-Lyon, CarMeN Laboratory, Inserm U1060, INSA Lyon, INRA U1397, Université Claude Bernard Lyon 1, Villeurbanne, France. 4. Graduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil. 5. Departamento de Patologia Básica, Federal University of Paraná (UFPR), Curitiba, PR, Brazil. 6. Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil. 7. Department of Nephrology, Centre Hopitalier Lyon Sud, INSERM 1060, CENS, Université de Lyon, Lyon, France. 8. Graduate Program in Nutrition Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil.
Abstract
PURPOSE: Uremic toxins produced by gut microbiota (indoxyl sulfate-IS, p-cresyl sulfate-p-CS, and indole-3-acetic acid-IAA) accumulate in hemodialysis (HD) patients and exhibit potent inflammatory effects. However, the impact of these toxins on nuclear E2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) expression in HD patients remains poorly defined. The aim of this study was to evaluate the association between uremic toxins and Nrf2/NF-κB expression in vitro (RAW 264.7 macrophage-like cells) and in peripheral blood mononuclear cells from HD patients. METHODS: Uremic toxins, C-reactive protein (CRP), interleukin-6 (IL-6) and malondialdehyde (MDA) levels were measured in fifteen HD patients and nine healthy individuals. RAW 264.7 macrophage-like cells were incubated with IS, as a prototype of protein-bound uremic toxin. Nrf2 and NF-κB expressions were analyzed by RT-qPCR. RESULTS: HD patients presented high levels of inflammatory markers, MDA and uremic toxins. In addition, they presented high NF-κB and low Nrf2 expression. Uremic toxins were positively correlated with NF-κB expression (IS, ρ = 0.58, p < 0.003; p-CS, ρ = 0.71, p < 0.001; IAA, ρ = 0.62, p < 0.001) and negatively with Nrf2 (IS, ρ = - 0.48, p = 0.01; p-CS, ρ = - 0.46, p < 0.02). Uremic toxins also exhibited positive correlations with CRP and MDA levels. Multivariate analysis revealed that p-CS is a determinant factor of NF-κB expression. In RAW 264.7 culture, NF-κB mRNA expression was stimulated by IS, while Nrf2 was downregulated. CONCLUSIONS: Thus, uremic toxins may stimulate NF-κB mRNA and decrease Nrf2 expression in HD patients and, consequently, trigger inflammation and oxidative stress.
PURPOSE: Uremic toxins produced by gut microbiota (indoxyl sulfate-IS, p-cresyl sulfate-p-CS, and indole-3-acetic acid-IAA) accumulate in hemodialysis (HD) patients and exhibit potent inflammatory effects. However, the impact of these toxins on nuclear E2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) expression in HDpatients remains poorly defined. The aim of this study was to evaluate the association between uremic toxins and Nrf2/NF-κB expression in vitro (RAW 264.7 macrophage-like cells) and in peripheral blood mononuclear cells from HDpatients. METHODS: Uremic toxins, C-reactive protein (CRP), interleukin-6 (IL-6) and malondialdehyde (MDA) levels were measured in fifteen HDpatients and nine healthy individuals. RAW 264.7 macrophage-like cells were incubated with IS, as a prototype of protein-bound uremic toxin. Nrf2 and NF-κB expressions were analyzed by RT-qPCR. RESULTS:HDpatients presented high levels of inflammatory markers, MDA and uremic toxins. In addition, they presented high NF-κB and low Nrf2 expression. Uremic toxins were positively correlated with NF-κB expression (IS, ρ = 0.58, p < 0.003; p-CS, ρ = 0.71, p < 0.001; IAA, ρ = 0.62, p < 0.001) and negatively with Nrf2 (IS, ρ = - 0.48, p = 0.01; p-CS, ρ = - 0.46, p < 0.02). Uremic toxins also exhibited positive correlations with CRP and MDA levels. Multivariate analysis revealed that p-CS is a determinant factor of NF-κB expression. In RAW 264.7 culture, NF-κB mRNA expression was stimulated by IS, while Nrf2 was downregulated. CONCLUSIONS: Thus, uremic toxins may stimulate NF-κB mRNA and decrease Nrf2 expression in HDpatients and, consequently, trigger inflammation and oxidative stress.
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