PMID- 32764271
OWN - NLM
STAT- MEDLINE
DCOM- 20210308
LR  - 20210308
IS  - 2072-6651 (Electronic)
IS  - 2072-6651 (Linking)
VI  - 12
IP  - 8
DP  - 2020 Aug 5
TI  - Indoxyl Sulfate Contributes to Adipose Tissue Inflammation through the Activation 
      of NADPH Oxidase.
LID - 10.3390/toxins12080502 [doi]
LID - 502
AB  - 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-alpha 
      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.
FAU - Tanaka, Shoma
AU  - Tanaka S
AUID- ORCID: 0000-0002-9481-9265
AD  - Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 
      Kumamoto University, Kumamoto 8620973, Japan.
FAU - Watanabe, Hiroshi
AU  - Watanabe H
AD  - Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 
      Kumamoto University, Kumamoto 8620973, Japan.
FAU - Nakano, Takehiro
AU  - Nakano T
AD  - Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 
      Kumamoto University, Kumamoto 8620973, Japan.
FAU - Imafuku, Tadashi
AU  - Imafuku T
AD  - Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 
      Kumamoto University, Kumamoto 8620973, Japan.
FAU - Kato, Hiromasa
AU  - Kato H
AD  - Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 
      Kumamoto University, Kumamoto 8620973, Japan.
FAU - Tokumaru, Kai
AU  - Tokumaru K
AD  - Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 
      Kumamoto University, Kumamoto 8620973, Japan.
FAU - Arimura, Nanaka
AU  - Arimura N
AD  - Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 
      Kumamoto University, Kumamoto 8620973, Japan.
FAU - Enoki, Yuki
AU  - Enoki Y
AUID- ORCID: 0000-0002-5934-0670
AD  - Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Tokyo 1058512, 
      Japan.
FAU - Maeda, Hitoshi
AU  - Maeda H
AD  - Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 
      Kumamoto University, Kumamoto 8620973, Japan.
FAU - Tanaka, Motoko
AU  - Tanaka M
AD  - Department of Nephrology, Akebono Clinic, Kumamoto 8614112, Japan.
FAU - Matsushita, Kazutaka
AU  - Matsushita K
AD  - Department of Nephrology, Akebono Clinic, Kumamoto 8614112, Japan.
FAU - Fukagawa, Masafumi
AU  - Fukagawa M
AD  - Division of Nephrology, Endocrinology and Metabolism, Tokai University School of 
      Medicine, Kanagawa 2591193, Japan.
FAU - Maruyama, Toru
AU  - Maruyama T
AD  - Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 
      Kumamoto University, Kumamoto 8620973, Japan.
LA  - eng
GR  - JP16H05114, JP20H03406/Japan Society for the Promotion of Science/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200805
PL  - Switzerland
TA  - Toxins (Basel)
JT  - Toxins
JID - 101530765
RN  - 0 (Adgre1 protein, mouse)
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Oxides)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Tnf protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 7440-44-0 (Carbon)
RN  - 90597-58-3 (AST 120)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - N187WK1Y1J (Indican)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Adipose Tissue/drug effects/*metabolism
MH  - Animals
MH  - Anti-Inflammatory Agents/pharmacology/therapeutic use
MH  - Calcium-Binding Proteins/metabolism
MH  - Carbon/pharmacology/therapeutic use
MH  - Chemokine CCL2/metabolism
MH  - Indican/*metabolism
MH  - Inflammation/chemically induced/drug therapy/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred ICR
MH  - NADPH Oxidases/*metabolism
MH  - Oxidative Stress/drug effects
MH  - Oxides/pharmacology/therapeutic use
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, G-Protein-Coupled/metabolism
MH  - Renal Insufficiency, Chronic/drug therapy/*metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC7472142
OTO - NOTNLM
OT  - AST-120
OT  - NADPH oxidase
OT  - adipocyte
OT  - chronic inflammation
OT  - indoxyl sulfate
OT  - reactive oxygen species
COIS- The authors declare no conflict of interest.
EDAT- 2020/08/09 06:00
MHDA- 2021/03/09 06:00
PMCR- 2020/08/01
CRDT- 2020/08/09 06:00
PHST- 2020/06/10 00:00 [received]
PHST- 2020/07/23 00:00 [revised]
PHST- 2020/08/03 00:00 [accepted]
PHST- 2020/08/09 06:00 [entrez]
PHST- 2020/08/09 06:00 [pubmed]
PHST- 2021/03/09 06:00 [medline]
PHST- 2020/08/01 00:00 [pmc-release]
AID - toxins12080502 [pii]
AID - toxins-12-00502 [pii]
AID - 10.3390/toxins12080502 [doi]
PST - epublish
SO  - Toxins (Basel). 2020 Aug 5;12(8):502. doi: 10.3390/toxins12080502.