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Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation

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Abstract

The gut microbiota has a crucial effect on regulating the intestinal mucosal immunity and maintaining intestinal homeostasis both in health and in disease state. Many effects are mediated by gut microbiota-derived metabolites and tryptophan, an essential aromatic amino acid, is considered important among many metabolites in the crosstalk between gut microbiota and the host. Kynurenine, serotonin, and indole derivatives are derived from the three major tryptophan metabolism pathways modulated by gut microbiota directly or indirectly. Aryl hydrocarbon receptor (AHR) is a cytoplasmic ligand-activated transcription factor involved in multiple cellular processes. Tryptophan metabolites as ligands can activate AHR signaling in various diseases such as inflammation, oxidative stress injury, cancer, aging-related diseases, cardiovascular diseases (CVD), and chronic kidney diseases (CKD). Accumulated uremic toxins in the body fluids of CKD patients activate AHR and affect disease progression. In this review, we will elucidate the relationship between gut microbiota-derived uremic toxins by tryptophan metabolism and AHR activation in CKD and its complications. This review will provide therapeutic avenues for targeting CKD and concurrently present challenges and opportunities for designing new therapeutic strategies against renal fibrosis.

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Abbreviations

AHR:

Aryl hydrocarbon receptor

AHRR:

AHR repressor protein

ARNT:

AHR nuclear translocator

CKD:

Chronic kidney disease

COX-2:

Cyclooxygenase-2

CVD:

Cardiovascular diseases

CYP:

Cytochrome P450 family

DKD:

Diabetic kidney disease

ESRD:

End-stage renal disease

I3A:

Indole-3-aldehyde

IAA:

Indole-3-acetic acid

IDO:

Indoleamine 2,3-dioxygenase

ILA:

Indole-3-lactic acid

IS:

Indoxyl sulfate

HIF:

Hypoxia-inducible transcription factor

NF-κB:

Nuclear factor kappa B

PAHs:

Polycyclic aromatic hydrocarbons

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

TF:

Tissue factor

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. 81603271, 81673578, 81872985) and National Key Research and Development Project of China (2019YFC1709405).

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  1. Jing-Ru Liu and Hua Miao are co-first authors.

Authors and Affiliations

  1. Faculty of Life Science, & Medicine, Northwest University, No. 229 Taibai North Road, Xi’an, 710069, Shaanxi, China

    Jing-Ru Liu, Hua Miao & Ying-Yong Zhao

  2. Department of Nephrology, Urumqi Chinese Medicine Hospital, No. 590 Fridenly South Road, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China

    De-Qiang Deng

  3. Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, Irvine, CA, 92897, USA

    Nosratola D. Vaziri

  4. Beijing Key Lab for Immune-Mediated Inflammatory Diseases, Department of Nephrology, Institute of Clinical Medical Science, China-Japan Friendship Hospital, Beijing, 100029, China

    Ping Li

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Liu, JR., Miao, H., Deng, DQ. et al. Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation. Cell. Mol. Life Sci. 78, 909–922 (2021). https://doi.org/10.1007/s00018-020-03645-1

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