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

DQ Chen, G Cao, H Chen, CP Argyopoulos… - Nature …, 2019 - nature.com
DQ Chen, G Cao, H Chen, CP Argyopoulos, H Yu, W Su, L Chen, DC Samuels, S Zhuang…
Nature communications, 2019nature.com
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) …
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.
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