Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan

Dan-Qian Chen, Gang Cao, Hua Chen, Christos P. Argyopoulos, Hui Yu, Wei Su, Lin Chen, David C. Samuels, Shougang Zhuang, George P. Bayliss, Shilin Zhao, Xiao-Yong Yu, Nosratola D. Vaziri, Ming Wang, Dan Liu, Jia-Rong Mao, Shi-Xing Ma, Jin Zhao, Yuan Zhang, You-Quan Shang, Huining Kang, Fei Ye, Xiao-Hong Cheng, Xiang-Ri Li, Li Zhang, Mei-Xia Meng, Yan Guo () and Ying-Yong Zhao ()
Additional contact information
Dan-Qian Chen: Northwest University
Gang Cao: Zhejiang Chinese Medical University
Hua Chen: Northwest University
Christos P. Argyopoulos: University of New Mexico
Hui Yu: University of New Mexico
Wei Su: Baoji Central Hospital
Lin Chen: Northwest University
David C. Samuels: Vanderbilt University Medical Center
Shougang Zhuang: Tongji University School of Medicine
George P. Bayliss: Brown University
Shilin Zhao: Vanderbilt University Medical Center
Xiao-Yong Yu: Affiliated Hospital of Shaanxi Institute of Traditional Chinese Medicine
Nosratola D. Vaziri: University of California Irvine
Ming Wang: Northwest University
Dan Liu: Northwest University
Jia-Rong Mao: Affiliated Hospital of Shaanxi Institute of Traditional Chinese Medicine
Shi-Xing Ma: Baoji Central Hospital
Jin Zhao: Department of Nephrology
Yuan Zhang: Department of Nephrology
You-Quan Shang: Baoji Central Hospital
Huining Kang: University of New Mexico
Fei Ye: Vanderbilt University Medical Center
Xiao-Hong Cheng: Affiliated Hospital of Shaanxi Institute of Traditional Chinese Medicine
Xiang-Ri Li: Beijing University of Chinese Medicine
Li Zhang: Department of Nephrology
Mei-Xia Meng: Department of Nephrology
Yan Guo: Northwest University
Ying-Yong Zhao: Northwest University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Early detection and accurate monitoring of chronic kidney disease (CKD) could improve care and retard progression to end-stage renal disease. Here, using untargeted metabolomics in 2155 participants including patients with stage 1–5 CKD and healthy controls, we identify five metabolites, including 5-methoxytryptophan (5-MTP), whose levels strongly correlate with clinical markers of kidney disease. 5-MTP levels decrease with progression of CKD, and in mouse kidneys after unilateral ureteral obstruction (UUO). Treatment with 5-MTP ameliorates renal interstitial fibrosis, inhibits IκB/NF-κB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperfusion injury, as well as in cultured human kidney cells. Overexpression of tryptophan hydroxylase-1 (TPH-1), an enzyme involved in 5-MTP synthesis, reduces renal injury by attenuating renal inflammation and fibrosis, whereas TPH-1 deficiency exacerbates renal injury and fibrosis by activating NF-κB and inhibiting Nrf2 pathways. Together, our results suggest that TPH-1 may serve as a target in the treatment of CKD.

Date: 2019
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DOI: 10.1038/s41467-019-09329-0

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