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

Abstract

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.

• Authors: Shoma Tanaka, Hiroshi Watanabe, Takehiro Nakano, Tadashi Imafuku, Hiromasa Kato, Kai Tokumaru, Nanaka Arimura, Yuki Enoki, Hitoshi Maeda, Motoko Tanaka, Kazutaka Matsushita, Masafumi Fukagawa, Toru Maruyama
• Journal: Toxins (Toxins (Basel)) Vol. 12 Issue 8 (08 05 2020) ISSN: 2072-6651 [Electronic] Switzerland
• PMID: 32764271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adgre1 protein, mouse
• Anti-Inflammatory Agents
• Calcium-Binding Proteins
• Ccl2 protein, mouse
• Chemokine CCL2
• Oxides
• Reactive Oxygen Species
• Receptors, G-Protein-Coupled
• Tnf protein, mouse
• Tumor Necrosis Factor-alpha
• Carbon
• AST 120
• NADPH Oxidases
• Indican

Topics

• 3T3-L1 Cells
• Adipose Tissue (drug effects, metabolism)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Calcium-Binding Proteins (metabolism)
• Carbon (pharmacology, therapeutic use)
• Chemokine CCL2 (metabolism)
• Indican (metabolism)
• Inflammation (chemically induced, drug therapy, metabolism)
• Male
• Mice
• Mice, Inbred ICR
• NADPH Oxidases (metabolism)
• Oxidative Stress (drug effects)
• Oxides (pharmacology, therapeutic use)
• Reactive Oxygen Species (metabolism)
• Receptors, G-Protein-Coupled (metabolism)
• Renal Insufficiency, Chronic (drug therapy, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)