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

Tanaka, Sonosuke; Watanabe, Hiroshi; Nakano, Tsutomu; Imafuku, Tadashi; Kato, Hiromasa; Tokumaru, Kai; Arimura, Nanaka; Enoki, Yuki; Maeda, Hitoshi; Tanaka, Motoko; Matsushita, Kazutaka; Fukagawa, Masafumi; Maruyama, Toru

doi:10.3390/toxins12080502

Cited by 20 publications

(20 citation statements)

References 33 publications

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“…In fact, recent reports have shown that these uremic toxins are not only involved in the progression of renal damage [16], but are also involved in CKD complications such as cardiovascular disease [17], muscle atrophy and weakness [18], osteoporosis [19], and cognitive decline [20]. The molecular mechanism responsible for the cellular damage caused by these uremic toxins involves the overproduction of reactive oxygen species (ROS) through the activation of NADPH oxidase after they are taken up into various cells via organic anion transporters (OATs) [21,22]. As mentioned above, ROS functions as an activator of mTORC1.…”

Section: Introductionmentioning

confidence: 99%

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

Nakano

Watanabe

Imafuku

et al. 2021

Toxins

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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.

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Section: Introductionmentioning

confidence: 99%

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

Nakano

Watanabe

Imafuku

et al. 2021

Toxins

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“…Interestingly, the metabolite indoxyl sulfate was elevated in gWAT from TejJ114 mice under CR. Indoxyl sulfate is a metabolite of L-tryptophan and is an established uremic- and cardio-toxin that has been linked to adipose tissue inflammation and oxidative stress ( Tanaka et al, 2020 ). Our principal component analysis (PCA) indicated that there is significant overlap in the metabolic profiles between TejJ89 and TejJ114 under AL feeding, and that the separation between strains becomes much more apparent following CR.…”

Section: Discussionmentioning

confidence: 99%

Strain-specific metabolic responses to long-term caloric restriction in female ILSXISS recombinant inbred mice

Mulvey

Wilkie

Borland

et al. 2021

Molecular and Cellular Endocrinology

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The role that genetic background may play in the responsiveness of organisms to interventions such as caloric restriction (CR) is underappreciated but potentially important. We investigated the impact of genetic background on a suite of metabolic parameters in female recombinant inbred ILSXISS mouse strains previously reported to show divergent lifespan responses to 40% CR (TejJ89-lifespan extension; TejJ48-lifespan unaffected; TejJ114-lifespan shortening). Body mass was reduced across all strains following 10 months of 40% CR, although this loss (relative to ad libitum controls) was greater in TejJ114 relative to the other strains. Gonadal white adipose tissue (gWAT) mass was similarly reduced across all strains following 40% CR, but brown adipose tissue (BAT) mass increased only in strains TejJ89 and TejJ48. Surprisingly, glucose tolerance was improved most notably by CR in TejJ114, while both strains TejJ89 and TejJ114 were hyperinsulinemic following CR relative to their AL controls. We subsequently undertook an unbiased metabolomic approach in gWAT and BAT tissue derived from strains TejJ89 and TejJ114 mice under AL and 40% CR. In gWAT from TejJ89 a significant reduction in several long chain unsaturated fatty acids was observed following 40% CR, but gWAT from TejJ114 appeared relatively unresponsive to CR with far fewer metabolites changing. Phosphatidylethanoloamine lipids within the BAT were typically elevated in TejJ89 following CR, while some phosphatidylglycerol lipids were decreased. However, BAT from strain TejJ114 again appeared unresponsive to CR. These data highlight strain-specific metabolic differences exist in ILSXISS mice following 40% CR. We suggest that precisely how different fat depots respond dynamically to CR may be an important factor in the variable longevity under 40% CR reported in these mice.

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“…AGP is generally recognized as an acute phase protein involved in immune responses. This abundant plasma protein is an immunomodulator induced by stressful conditions such as infections, and it protects adipose tissue from excessive inflammation induced by incresing plasma IS levels [15,16,25,26]. The authors speculate that the serum AGP may specifically refer to the gut function as a highly reliable indicator of disease activity in ulcerative colitis and diarrhea-predominant irritable bowel syndrome [17,27].…”

Section: Plos Onementioning

confidence: 99%

Serum indoxyl sulphate and its relation to albumin and α1-acid glycoprotein as a potential biomarkers of maternal intestinal metabolism during pregnancy and postpartum

et al. 2021

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Background Serum indoxyl sulfate (IS) levels depend on the production of indole in the gut. The biological effects of IS in the vascular bed could be confirmed by changes in the levels of individual serum proteins during normal pregnancy and in the postpartum period as compared with non-pregnant controls. Albumin (Alb) and α1-acid glycoprotein (AGP, orosomucoid) are the most abundant serum carrier proteins with potential interrelationships with serum levels of IS. Methods Serum levels of IS, Alb and AGP were measured in 84 pregnant women in the first, second and third trimester of pregnancy and in the postpartum period, as well as in non-pregnant controls (n = 20), using ultra-performance liquid chromatography (UPLC) coupled to mass spectrometry (IS), colorimetric assay (Alb) and immunoturbidimetric assay (AGP). Results The postpartum serum levels [mg/L] of IS were lower (p = 0.027) than in the second trimester (mean±SD: 0.85±0.39 vs 0.58±0.32). There were no differences in the IS to ALB ratio calculated in the three trimesters of pregnancy, the postpartum period, and in the non-pregnant controls. The IS/AGP ratio increased from the first to the second trimester (p = 0.039), and decreased in the postpartum period (p<0.05), when it was lower than in the second and third trimester. Conclusions The variability of the serum IS/AGP ratio during pregnancy and in the postpartum period may reflect shared involvement in the regulation of their intravascular relationships. The link between serum levels of IS derived from the gut and AGP could serve a potential biomarkers of maternal intestinal metabolism during pregnancy and postpartum.

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

Cited by 20 publications

References 33 publications

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

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

Strain-specific metabolic responses to long-term caloric restriction in female ILSXISS recombinant inbred mice

Serum indoxyl sulphate and its relation to albumin and α1-acid glycoprotein as a potential biomarkers of maternal intestinal metabolism during pregnancy and postpartum

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