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, and Zhao, Ying-Yong
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.