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Article

Indoxyl Sulfate Contributes to Adipose Tissue Inflammation through the Activation of NADPH Oxidase

1
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 8620973, Japan
2
Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Tokyo 1058512, Japan
3
Department of Nephrology, Akebono Clinic, Kumamoto 8614112, Japan
4
Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Kanagawa 2591193, Japan
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
Received: 10 June 2020 / Revised: 23 July 2020 / Accepted: 3 August 2020 / Published: 5 August 2020
Adipose tissue inflammation appears to be a risk factor for the progression of chronic kidney disease (CKD), but the effect of CKD on adipose tissue inflammation is poorly understood. The purpose of this study was to clarify the involvement of uremic toxins (indoxyl sulfate (IS), 3-indoleacetic acid, p-cresyl sulfate and kynurenic acid) on CKD-induced adipose tissue inflammation. IS induces monocyte chemoattractant protein-1 (MCP-1) expression and reactive oxygen species (ROS) production in the differentiated 3T3L-1 adipocyte. An organic anion transporter (OAT) inhibitor, an NADPH oxidase inhibitor or an antioxidant suppresses the IS-induced MCP-1 expression and ROS production, suggesting the OAT/NADPH oxidase/ROS pathway is involved in the action of IS. Co-culturing 3T3L-1 adipocytes and mouse macrophage cells showed incubating adipocytes with IS increased macrophage infiltration. An IS-overload in healthy mice increased IS levels, oxidative stress and MCP-1 expression in epididymal adipose tissue compared to unloaded mice. Using 5/6-nephrectomized mice, the administration of AST-120 suppressed oxidative stress and the expression of MCP-1, F4/80 and TNF-α in epididymal adipose tissue. These collective data suggest IS could be a therapeutic target for the CKD-related inflammatory response in adipose tissue, and that AST-120 could be useful for the treatment of IS-induced adipose tissue inflammation. View Full-Text
Keywords: indoxyl sulfate; adipocyte; chronic inflammation; AST-120; NADPH oxidase; reactive oxygen species indoxyl sulfate; adipocyte; chronic inflammation; AST-120; NADPH oxidase; reactive oxygen species
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MDPI and ACS Style

Tanaka, S.; Watanabe, H.; Nakano, T.; Imafuku, T.; Kato, H.; Tokumaru, K.; Arimura, N.; Enoki, Y.; Maeda, H.; Tanaka, M.; Matsushita, K.; Fukagawa, M.; Maruyama, T. Indoxyl Sulfate Contributes to Adipose Tissue Inflammation through the Activation of NADPH Oxidase. Toxins 2020, 12, 502. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080502

AMA Style

Tanaka S, Watanabe H, Nakano T, Imafuku T, Kato H, Tokumaru K, Arimura N, Enoki Y, Maeda H, Tanaka M, Matsushita K, Fukagawa M, Maruyama T. Indoxyl Sulfate Contributes to Adipose Tissue Inflammation through the Activation of NADPH Oxidase. Toxins. 2020; 12(8):502. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080502

Chicago/Turabian Style

Tanaka, Shoma, Hiroshi Watanabe, Takehiro Nakano, Tadashi Imafuku, Hiromasa Kato, Kai Tokumaru, Nanaka Arimura, Yuki Enoki, Hitoshi Maeda, Motoko Tanaka, Kazutaka Matsushita, Masafumi Fukagawa, and Toru Maruyama. 2020. "Indoxyl Sulfate Contributes to Adipose Tissue Inflammation through the Activation of NADPH Oxidase" Toxins 12, no. 8: 502. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080502

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