scholarly journals Acute Exposure to Indoxyl Sulfate Impairs Endothelium-Dependent Vasorelaxation in Rat Aorta

2019 ◽  
Vol 20 (2) ◽  
pp. 338 ◽  
Author(s):  
Takayuki Matsumoto ◽  
Keisuke Takayanagi ◽  
Mihoka Kojima ◽  
Kumiko Taguchi ◽  
Tsuneo Kobayashi
Keyword(s):  
Oxidative Stress ◽  
Gut Microbiota ◽  
Nadph Oxidase ◽  
Vascular Function ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Indoxyl Sulfate ◽  
Transient Receptor Potential Vanilloid ◽  
Ionophore A23187 ◽  
Anion Transporter

Gut microbiota are emerging as potential contributors to the regulation of host homeostasis. Dysbiosis of the gut microbiota associated with increased intestinal permeability facilitates the passage of endotoxins and other microbial products, including indoxyl sulfate in the circulation. Although an emerging body of evidence has suggested that indoxyl sulfate is a key substance for the development of chronic kidney disease, few studies have investigated the direct association of indoxyl sulfate with vascular function. We hypothesized that indoxyl sulfate adversely affects vascular function. Aortas isolated from male Wistar rat were examined in the presence or absence of indoxyl sulfate to assess the vascular function, including vasorelaxation and vasocontraction. Indoxyl sulfate (vs. vehicle) (1) decreased vasorelaxation induced by acetylcholine (ACh) but not by sodium nitroprusside; (2) had no significant alterations of noradrenaline-induced vasocontraction in the absence and presence of endothelium; (3) decreased adenylyl cyclase activator (forskolin)-induced vasorelaxation, while such a difference was eliminated by endothelial denudation; and (4) decreased vasorelaxations induced by calcium ionophore (A23187) and transient receptor potential vanilloid 4 agonist (GSK1016790A). The indoxyl sulfate-induced decrease in the vasorelaxations induced by ACh and A23187 increased by cell-permeant superoxide dismutase or by organic anion transporter inhibitor. However, apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, had no effects on vasorelaxations induced by ACh, A23187, forskolin, and GSK1016790A in the presence of indoxyl sulfate. These results suggest that indoxyl sulfate directly affects the vascular function, particularly, endothelium-dependent vasorelaxation, and this effect may be attributable to increased oxidative stress after cell transportion via organic anion transporter, and such increased oxidative stress may not be attributable to activation of NADPH oxidase activation.

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

Toxins ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 502
Author(s):  
Shoma Tanaka ◽  
Hiroshi Watanabe ◽  
Takehiro Nakano ◽  
Tadashi Imafuku ◽  
Hiromasa Kato ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Adipose Tissue ◽  
Nadph Oxidase ◽  
Organic Anion ◽  
Indoxyl Sulfate ◽  
Epididymal Adipose Tissue ◽  
Ros Production ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Anion Transporter

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.

scholarly journals Indoxyl Sulfate Contributes to mTORC1-Induced Renal Fibrosis via The OAT/NADPH Oxidase/ROS Pathway

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 909
Author(s):  
Takehiro Nakano ◽  
Hiroshi Watanabe ◽  
Tadashi Imafuku ◽  
Kai Tokumaru ◽  
Issei Fujita ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Indoxyl Sulfate ◽  
Uremic Toxin ◽  
Mesenchymal Transition ◽  
Anion Transporter

Activation of mTORC1 (mechanistic target of rapamycin complex 1) in renal tissue has been reported in chronic kidney disease (CKD)-induced renal fibrosis. However, the molecular mechanisms responsible for activating mTORC1 in CKD pathology are not well understood. The purpose of this study was to identify the uremic toxin involved in mTORC1-induced renal fibrosis. Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS) caused significant activation of mTORC1 in human kidney 2 cells (HK-2 cells). This IS-induced mTORC1 activation was inhibited in the presence of an organic anion transporter inhibitor, a NADPH oxidase inhibitor, and an antioxidant. IS also induced epithelial–mesenchymal transition of tubular epithelial cells (HK-2 cells), differentiation of fibroblasts into myofibroblasts (NRK-49F cells), and inflammatory response of macrophages (THP-1 cells), which are associated with renal fibrosis, and these effects were inhibited in the presence of rapamycin (mTORC1 inhibitor). In in vivo experiments, IS overload was found to activate mTORC1 in the mouse kidney. The administration of AST-120 or rapamycin targeted to IS or mTORC1 ameliorated renal fibrosis in Adenine-induced CKD mice. The findings reported herein indicate that IS activates mTORC1, which then contributes to renal fibrosis. Therapeutic interventions targeting IS and mTORC1 could be effective against renal fibrosis in CKD.

scholarly journals Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

2019 ◽  
Vol 116 (32) ◽  
pp. 16105-16110 ◽  
Author(s):  
Jitske Jansen ◽  
Katja Jansen ◽  
Ellen Neven ◽  
Ruben Poesen ◽  
Amr Othman ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Gut Microbiome ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Indoxyl Sulfate ◽  
Regulation Mechanism ◽  
Uremic Toxin ◽  
Proximal Tubule Cell ◽  
Anion Secretion ◽  
Anion Transporter

Membrane transporters and receptors are responsible for balancing nutrient and metabolite levels to aid body homeostasis. Here, we report that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, metabolite levels through EGF receptors and downstream signaling to induce their secretion by up-regulating the organic anion transporter-1 (OAT1). Remote metabolite sensing and signaling was observed in kidneys from healthy volunteers and rats in vivo, leading to induced OAT1 expression and increased removal of indoxyl sulfate, a prototypical microbiome-derived metabolite and uremic toxin. Using 2D and 3D human proximal tubule cell models, we show that indoxyl sulfate induces OAT1 via AhR and EGFR signaling, controlled by miR-223. Concomitantly produced reactive oxygen species (ROS) control OAT1 activity and are balanced by the glutathione pathway, as confirmed by cellular metabolomic profiling. Collectively, we demonstrate remote metabolite sensing and signaling as an effective OAT1 regulation mechanism to maintain plasma metabolite levels by controlling their secretion.

scholarly journals Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney

2002 ◽  
Vol 61 (5) ◽  
pp. 1760-1768 ◽  
Author(s):  
Tsuneo Deguchi ◽  
Sumio Ohtsuki ◽  
Masaki Otagiri ◽  
Hitomi Takanaga ◽  
Hiroshi Asaba ◽  
...  
Keyword(s):  
Organic Anion ◽  
Organic Anion Transporter ◽  
Indoxyl Sulfate ◽  
Anion Transporter ◽  
Organic Anion Transporter 3

scholarly journals P0946OXIDATIVE STRESS AND HEME METABOLISM IN RED BLOOD CELLS FROM HEMODIALYSIS PATIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Gabriela Ferreira Dias ◽  
Gabriela Bohnen ◽  
Nadja Grobe ◽  
Xia Tao ◽  
Roberto Pecoits-Filho ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Organic Anion ◽  
Fold Increase ◽  
Organic Anion Transporter ◽  
Ros Generation ◽  
Heme Oxygenase 1 ◽  
Anion Transporter ◽  
Before And After

Abstract Background and Aims We have previously described that indoxyl sulfate promotes red blood cells (RBC) ROS generation through organic anion transporter 2 as well as NADPH oxidase activity-dependent and GSH-independent mechanisms (Dias et al., 2018). However, there is little information regarding pathways of antioxidant balance to protect RBC from extensive oxidative stress that occurs during hemodialysis (HD). Intracellular free heme is degraded by Heme Oxygenase 1 (HO-1), which is regarded as the major cytoprotective enzyme (Maines, 1988; Gozzelino et al., 2010). In the current study, we assessed HO-1 activity and ROS production in RBC from healthy subjects and hemodialysis (HD) patients before and after HD. Method Blood was drawn from 6 healthy individuals (CON-RBC) and 6 HD patients (HD-RBC) before (pre/HD-RBC) and after high flux HD (post/HD-RBC). Isolated RBC were stained with DCFH-DA (Abcam) for ROS measurements. To quantify HO-1, RBC were incubated with anti-HO-1 antibody (Abcam) and m-IgGκ BP-CFL 488 (Santa Cruz Biotechnology) as a secondary antibody. Samples were analyzed by flow cytometry. Results Our results show a 4-fold increase in ROS levels in pre/HD-RBC compared to CON-RBC. ROS levels were even further increased by 1.65-fold after HD treatment in post/HD-RBC (Figure 1). Both pre/HD-RBC and post/HD-RBC showed a similarly significant increase of 3.3-fold in HO-1 compared to CON-RBC. (Figure 1). Conclusion High levels of HO-1 may represent a defense against oxidative stress that occurs in ESKD and particularly during the HD session. Further research is needed to evaluate whether HO-1 overexpression could accelerate heme degradation and contribute to renal anemia.

scholarly journals Impact of Camellia japonica Bee Pollen Polyphenols on Hyperuricemia and Gut Microbiota in Potassium Oxonate-Induced Mice

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2665
Author(s):  
Yuanyuan Xu ◽  
Xirong Cao ◽  
Haoan Zhao ◽  
Erlin Yang ◽  
Yue Wang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Glucose Transporter ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Nuclear Factor Κb ◽  
Organic Anion Transporter ◽  
Camellia Japonica ◽  
Bee Pollen ◽  
Anion Transporter ◽  
Potassium Oxonate

Camellia japonica bee pollen is one of the major types of bee pollen in China and exhibits antioxidant and anti-inflammatory activities. The aims of our study were to evaluate the effects and the possible mechanism of Camellia japonica bee pollen polyphenols on the treatment of hyperuricemia induced by potassium oxonate (PO). The results showed that Camellia japonica bee pollen ethyl acetate extract (CPE-E) owned abundant phenolic compounds and strong antioxidant capabilities. Administration with CPE-E for two weeks greatly reduced serum uric acid and improved renal function. It inhibited liver xanthine oxidase (XOD) activity and regulated the expression of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1) and ATP-binding cassette superfamily gmember 2 (ABCG2) in kidneys. Moreover, CPE-E suppressed the activation of the toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in PO-treated mice, and related inflammatory cytokines were reduced. CPE-E also modulated gut microbiota structure, showing that the abundance of Lactobacillus and Clostridiaceae increased in hyperuicemic mice. This study was conducted to explore the protective effect of CPE-E on hyperuricemia and provide new thoughts for the exploitation of Camellia japonica bee pollen.

Rat Organic Anion Transporter 3 (rOAT3) is Responsible for Brain-to-Blood Efflux of Homovanillic Acid at the Abluminal Membrane of Brain Capillary Endothelial Cells

2003 ◽  
Vol 23 (4) ◽  
pp. 432-440 ◽  
Author(s):  
Shinobu Mori ◽  
Hitomi Takanaga ◽  
Sumio Ohtsuki ◽  
Tsuneo Deguchi ◽  
Young-Sook Kang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Homovanillic Acid ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Indoxyl Sulfate ◽  
Brain Capillary ◽  
Anion Transporter ◽  
Capillary Endothelial Cells ◽  
Organic Anion Transporter 3 ◽  
The Brain

The mechanism that removes homovanillic acid (HVA), an end metabolite of dopamine, from the brain is still poorly understood. The purpose of this study is to identify and characterize the brain-to-blood HVA efflux transporter at the rat blood–brain barrier (BBB). Using the Brain Efflux Index method, the apparent in vivo efflux rate constant of [3H]HVA from the brain, keff, was determined to be 1.69 × 10–2 minute–1. This elimination was significantly inhibited by para-aminohippuric acid (PAH), benzylpenicillin, indoxyl sulfate, and cimetidine, suggesting the involvement of rat organic anion transporter 3 (rOAT3). rOAT3-expressing oocytes exhibited [3H]HVA uptake (Km = 274 μmol/L), which was inhibited by several organic anions, such as PAH, indoxyl sulfate, octanoic acid, and metabolites of monoamine neurotransmitters. Neurotransmitters themselves did not affect the uptake. Furthermore, immunohistochemical analysis suggested that rOAT3 is localized at the abluminal membrane of brain capillary endothelial cells. These results provide the first evidence that rOAT3 is expressed at the abluminal membrane of the rat BBB and is involved in the brain-to-blood transport of HVA. This HVA efflux transport system is likely to play an important role in controlling the level of HVA in the CNS.

scholarly journals SLC22 Transporters in the Fly Renal System Regulate Response to Oxidative Stress In Vivo

2021 ◽  
Vol 22 (24) ◽  
pp. 13407
Author(s):  
Patrick Zhang ◽  
Priti Azad ◽  
Darcy C. Engelhart ◽  
Gabriel G. Haddad ◽  
Sanjay K. Nigam
Keyword(s):  
Oxidative Stress ◽  
Fat Body ◽  
Organic Anion ◽  
Malpighian Tubule ◽  
Human Kidney ◽  
Organic Anion Transporter ◽  
In Vivo Studies ◽  
Anion Transporter ◽  
Renal System

Several SLC22 transporters in the human kidney and other tissues are thought to regulate endogenous small antioxidant molecules such as uric acid, ergothioneine, carnitine, and carnitine derivatives. These transporters include those from the organic anion transporter (OAT), OCTN/OCTN-related, and organic cation transporter (OCT) subgroups. In mammals, it has been difficult to show a clear in vivo role for these transporters during oxidative stress. Ubiquitous knockdowns of related Drosophila SLC22s—including transporters homologous to those previously identified by us in mammals such as the “Fly-Like Putative Transporters” FLIPT1 (SLC22A15) and FLIPT2 (SLC22A16)—have shown modest protection against oxidative stress. However, these fly transporters tend to be broadly expressed, and it is unclear if there is an organ in which their expression is critical. Using two tissue-selective knockdown strategies, we were able to demonstrate much greater and longer protection from oxidative stress compared to previous whole fly knockdowns as well as both parent and WT strains (CG6126: p < 0.001, CG4630: p < 0.01, CG16727: p < 0.0001 and CG6006: p < 0.01). Expression in the Malpighian tubule and likely other tissues as well (e.g., gut, fat body, nervous system) appear critical for managing oxidative stress. These four Drosophila SLC22 genes are similar to human SLC22 transporters (CG6126: SLC22A16, CG16727: SLC22A7, CG4630: SLC22A3, and CG6006: SLC22A1, SLC22A2, SLC22A3, SLC22A6, SLC22A7, SLC22A8, SLC22A11, SLC22A12 (URAT1), SLC22A13, SLC22A14)—many of which are highly expressed in the kidney. Consistent with the Remote Sensing and Signaling Theory, this indicates an important in vivo role in the oxidative stress response for multiple SLC22 transporters within the fly renal system, perhaps through interaction with SLC22 counterparts in non-renal tissues. We also note that many of the human relatives are well-known drug transporters. Our work not only indicates the importance of SLC22 transporters in the fly renal system but also sets the stage for in vivo studies by examining their role in mammalian oxidative stress and organ crosstalk.

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