Indoxyl Sulfate (IS), also known as 3-indoxylsulfate and 3-indoxylsulfuric acid, is a metabolite of dietary L-tryptophan that acts as a cardiotoxin and uremic toxin[1]. Indoxyl Sulfate is taken up by proximal tubular cells through organic anion transporters (OAT1, OAT3), and it induces reactive oxygen species (ROS) with impairment of cellular antioxidative system[2-3].
Indoxyl Sulfate (62.5-1000μM;24h) induces intestinal damage via inhibiting mitophagic flux in Caco2 cells[4]. Indoxyl Sulfate (1 mM;12 h) induces fibrotic responses of tubular epithelial cells, renal fibroblasts, and macrophages via mTORC1 signaling [5]. Indoxyl Sulfate (1 mM;24 h) induces monocyte chemoattractant protein-1 (MCP-1) expression and reactive oxygen species (ROS) production in the differentiated 3T3L-1 adipocyte[6].
After injection of Indoxyl Sulfate (100 mg/kg; i.p; 8 weeks), the intestinal macroscopical damage and permeability of mice increased, and the serum Indoxyl Sulfate level increased [4]. Indoxyl Sulfate (10-3 M, 60 min) augments ET-1-induced contraction in rat aortae [7]. Indoxyl Sulfate (200 mg/kg/day of Indoxyl Sulfate in water) downregulates renal expression of Nrf2 through activation of NF-κB, followed by downregulation of HO-1 and NQO1 and increased production of ROS[8]. Indoxyl Sulfate increased endothelin-1-induced contraction but had no effect on phenylephrine, thromboxane analog, or isotonic K+-induced renal arterial contractions[9].
硫酸吲哚酚(Indoxyl sulfate (IS)),又称3-吲哚酚硫酸和3-吲哚酚硫酸,是膳食l -色氨酸的代谢物,具有心脏毒素和尿毒症毒素的作用[1]。Indoxyl Sulfate (IS)通过有机阴离子转运体(OAT1, OAT3)被近端小管细胞吸收,诱导活性氧(ROS),损害细胞抗氧化系统[2-3]。
Indoxyl Sulfate (62.5 ~ 1000μM;24h)通过抑制Caco2细胞的有丝分裂通量诱导肠道损伤[4]。Indoxyl Sulfate (1 mM;12 h)通过mTORC1信号传导诱导小管上皮细胞、肾成纤维细胞和巨噬细胞的纤维化反应[5]。Indoxyl Sulfate (1 mM;24 h)诱导分化的3T3L-1脂肪细胞单核细胞趋化蛋白-1 (MCP-1)表达和活性氧(ROS)产生[6]。
注射Indoxyl Sulfate后(100 mg/kg; i.p; 8 weeks), 小鼠肠道宏观损伤和通透性增加,血清Indoxyl Sulfate水平升高[4]。硫酸吲哚酚(10-3 M, 60 min)增强ET -1诱导的大鼠主动脉收缩[7]。硫酸吲哚酚(200 mg/kg/day of Indoxyl Sulfate in water)通过激活NF-κB下调肾脏Nrf2的表达,随后下调HO-1和NQO1,增加ROS的产生[8]。硫酸吲哚酚增加内皮素-1诱导的收缩,但对苯肾上腺素、血栓素类似物或等渗K+诱导的肾动脉收缩没有影响[9]。
参考文献:
[1]. Lano G, Burtey S, et,al. Indoxyl Sulfate, a Uremic Endotheliotoxin. Toxins (Basel). 2020 Apr 5;12(4):229. doi: 10.3390/toxins12040229. PMID: 32260489; PMCID: PMC7232210.
[2]. Niwa T, Shimizu H. Indoxyl sulfate induces nephrovascular senescence. J Ren Nutr. 2012 Jan;22(1):102-6. doi: 10.1053/j.jrn.2011.10.032. PMID: 22200425.
[3]. Niwa T. Indoxyl sulfate is a nephro-vascular toxin. J Ren Nutr. 2010 Sep;20(5 Suppl):S2-6. doi: 10.1053/j.jrn.2010.05.002. PMID: 20797565.
[4]. Huang Y, Zhou J, et,al. Indoxyl sulfate induces intestinal barrier injury through IRF1-DRP1 axis-mediated mitophagy impairment. Theranostics. 2020 Jun 5;10(16):7384-7400. doi: 10.7150/thno.45455. PMID: 32641998; PMCID: PMC7330852.
[5]. Nakano T, Watanabe H, et,al.Indoxyl Sulfate Contributes to mTORC1-Induced Renal Fibrosis via The OAT/NADPH Oxidase/ROS Pathway. Toxins (Basel). 2021 Dec 18;13(12):909. doi: 10.3390/toxins13120909. PMID: 34941746; PMCID: PMC8706756.
[6]. Tanaka S, Watanabe H, et,al. Indoxyl Sulfate Contributes to Adipose Tissue Inflammation through the Activation of NADPH Oxidase. Toxins (Basel). 2020 Aug 5;12(8):502. doi: 10.3390/toxins12080502. PMID: 32764271; PMCID: PMC7472142.
[7]. Matsumoto T, Takayanagi K, et,al. Indoxyl sulfate enhances endothelin-1-induced contraction via impairment of NO/cGMP signaling in rat aorta. Pflugers Arch. 2021 Aug;473(8):1247-1259. doi: 10.1007/s00424-021-02581-8. Epub 2021 May 22. Erratum in: Pflugers Arch. 2021 Jun 17;: PMID: 34021781.
[8]. Bolati D, Shimizu H, et,al. Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB. BMC Nephrol. 2013 Mar 4;14:56. doi: 10.1186/1471-2369-14-56. PMID: 23496811; PMCID: PMC3599003.
[9]. Matsumoto T, Taguchi N, et,al. Indoxyl sulfate decreases uridine adenosine tetraphosphate-induced contraction in rat renal artery. Pflugers Arch. 2022 Dec;474(12):1285-1294. doi: 10.1007/s00424-022-02755-y. Epub 2022 Oct 1. PMID: 36181534.
| Cell experiment [1]: | |
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Cell lines |
Caco2 cells |
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Preparation Method |
Cells treated with various concentrations of Indoxyl Sulfate for 24 hours. |
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Reaction Conditions |
62.5-1000μM;24h |
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Applications |
Indoxyl Sulfate (IS) induces intestinal damage via inhibiting mitophagic flux in Caco2 cells. |
| Animal experiment [2]: | |
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Animal models |
C57BL/6J mice |
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Preparation Method |
Mice were intraperitoneally injected with Indoxyl Sulfate (100 mg/kg) daily for 8 weeks. |
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Dosage form |
100 mg/kg; i.p; 8 weeks |
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Applications |
After injection of Indoxyl Sulfate, the intestinal macroscopical damage and permeability of mice increased, and the serum Indoxyl Sulfate level increased. |
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参考文献: [1]. Huang Y, Zhou J, et,al. Indoxyl sulfate induces intestinal barrier injury through IRF1-DRP1 axis-mediated mitophagy impairment. Theranostics. 2020 Jun 5;10(16):7384-7400. doi: 10.7150/thno.45455. PMID: 32641998; PMCID: PMC7330852. |
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