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Chen, Dan-Qian; Cao, Gang; Chen, Hua; Argyopoulos, Christos P; Yu, Hui; Su, Wei; Chen, Lin; Samuels, David C; Zhuang, Shougang; Bayliss, George P; Zhao, Shilin; Yu, Xiao-Yong; Vaziri, Nosratola D; Wang, Ming; Liu, Dan; Mao, Jia-Rong; Ma, Shi-Xing; Zhao, Jin; Zhang, Yuan; Shang, You-Quan; Kang, Huining; Ye, Fei; Cheng, Xiao-Hong; Li, Xiang-Ri; Zhang, Li; Meng, Mei-Xia; Guo, Yan; Zhao, Ying-Yong
Nature communications, 04/2019, Volume: 10, Issue: 1Journal Article
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.
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