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, Ying-Yong Zhao, 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, Ying-Yong Zhao
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.
Conflict of interest statement
The authors declare no competing interests.
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References
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