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Blockade of Indoleamine 2,3-Dioxygenase attenuates lipopolysaccharide-induced kidney injury by inhibiting TLR4/NF-κB signaling

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Abstract

Blockade of indoleamine 2,3-dioxygenase (IDO) has been shown to alleviate lipopolysaccharide (LPS)-induced endotoxic shock and reduce sepsis mortality, but its effect on LPS-induced kidney damage has not been reported. Herein, we established a mouse kidney injury model by intraperitoneal injection of 10 mg/kg LPS and established an in vitro renal tubular epithelial cell injury model by stimulating TCMK-1 cells with 10 mg/L LPS. We found that pretreatment with 1-methyl tryptophan (1-MT), an IDO inhibitor, significantly improved LPS-induced mouse survival, and IDO knockout (KO) mice also had higher survival rates after LPS exposure than wild-type mice. At the same time, IDO KO or pretreatment with 1-MT not only reduced serum creatinine, blood urea nitrogen, renal tubular injury pathological score, but also inflammatory factors and oxidative stress status in serum or kidney of LPS-exposed mice. In vitro, blockade of IDO with 1-MT significantly inhibited LPS-induced apoptosis, inflammation and oxidative stress in TCMK-1 cells. In addition, blockade of IDO significantly inhibited LPS-activated TLR4/NF-κB signaling pathway in kidney of mice or in TCMK-1 cells. In conclusion, our results suggested that blockade of IDO attenuated kidney inflammation, apoptosis and oxidative stress to protect against LPS-induced septic kidney injury via inhibiting the TLR4/NF-κB signaling pathway.

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Data availability statement

The datasets generated and/or used during the present study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by 2023 Dongguan Social Development Science and Technology Project (general project) (Grant/Award Number: 20231800904482).

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Authors and Affiliations

  1. Department of Emergency, Dongguan Binhaiwan Central Hospital, Dongguan City, China

    Weiguang Wu, Zijing Lin & Jianhui Yan

  2. Department of Critical Medicine, Shenzhen Luohu District People’s Hospital, Shenzhen City, China

    Weixiong Zhong

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  1. Weiguang Wu
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  2. Weixiong Zhong
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  3. Zijing Lin
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  4. Jianhui Yan
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Contributions

JY: conceptualization, methodology, writing—original draft. WW: performed the experiments, writing—original draft. WZ and ZL: analyzed the data.

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Correspondence to Jianhui Yan.

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Supplementary Information

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10157_2023_2332_MOESM1_ESM.tif

Supplementary file1 IDO protein expression in different groups of kidney tissues. (A) Representative IDO protein immunohistochemical staining images in kidney of different group at 12 hours after LPS exposure. (B) IDO positive cells in kidney of different group were compared at 12 hours after LPS exposure. (C) Representative protein bands of IDO protein in kidney tissues of different group at 12 hours after LPS exposure. 10 mice in each group. *** P<0.001 vs Control group, and ### P<0.001 vs WT group. (TIF 1325 KB)

10157_2023_2332_MOESM2_ESM.tif

Supplementary file2 IDO protein expression in TCMK-1 cells after different treatment. (A) Expression of IDO protein in TCMK-1 cells stimulated with different concentrations of LPS for 8 hours using immunoblotting. (B) Expression of IDO protein in TCMK-1 cells stimulated with 10 mg/L LPS for different hours using immunoblotting. (C) TCMK-1 were stimulated with 10 mg/L LPS for 8 hours, and one replicate was added 1mM of 1-MT at 12 h before LPS onset. Cells were harvested to detect IDO protein expression using immunoblotting. 3 independent repetitions of each test. *** P<0.001 vs Solvent group (0 mg/L LPS or 10 mg/L LPS treat for 0 hours), and ### P<0.001 vs LPS group. (TIF 275 KB)

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Wu, W., Zhong, W., Lin, Z. et al. Blockade of Indoleamine 2,3-Dioxygenase attenuates lipopolysaccharide-induced kidney injury by inhibiting TLR4/NF-κB signaling. Clin Exp Nephrol 27, 495–505 (2023). https://doi.org/10.1007/s10157-023-02332-2

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  • DOI: https://doi.org/10.1007/s10157-023-02332-2

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