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

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 Commun

journal_title

Nature communications

authors

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,G

doi

10.1038/s41467-019-09329-0

subject

Has Abstract

pub_date

2019-04-01 00:00:00

pages

1476

issue

1

issn

2041-1723

pii

10.1038/s41467-019-09329-0

journal_volume

10

pub_type

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