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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Chen DQ,Cao G,Chen H,Argyopoulos CP,Yu H,Su W,Chen L,Samuels DC,Zhuang S,Bayliss GP,Zhao S,Yu XY,Vaziri ND,Wang M,Liu D,Mao JR,Ma SX,Zhao J,Zhang Y,Shang YQ,Kang H,Ye F,Cheng XH,Li XR,Zhang L,Meng MX,Gdoi
10.1038/s41467-019-09329-0subject
Has Abstractpub_date
2019-04-01 00:00:00pages
1476issue
1issn
2041-1723pii
10.1038/s41467-019-09329-0journal_volume
10pub_type
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