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Gene and protein expressions and metabolomics exhibit activated redox signaling
and wnt/?-catenin pathway are associated with metabolite dysfunction in patients
with chronic kidney disease
#MMPMID28343144
Chen DQ
; Cao G
; Chen H
; Liu D
; Su W
; Yu XY
; Vaziri ND
; Liu XH
; Bai X
; Zhang L
; Zhao YY
Redox Biol
2017[Aug]; 12
(?): 505-521
PMID28343144
show ga
Changes in plasma concentration of small organic metabolites could be due to
their altered production or urinary excretion and changes in their urine
concentration may be due to the changes in their filtered load, tubular
reabsorption, and/or altered urine volume. Therefore, these factors should be
considered in interpretation of the changes observed in plasma or urine of the
target metabolite(s). Fasting plasma and urine samples from 180 CKD patients and
120 age-matched healthy controls were determined by UPLC-HDMS-metabolomics and
quantitative real-time RT-PCR techniques. Compared with healthy controls,
patients with CKD showed activation of NF-?B and up-regulation of
pro-inflammatory and pro-oxidant mRNA and protein expression as well as
down-regulation of Nrf2-associated anti-oxidant gene mRNA and protein expression,
accompanied by activated canonical Wnt/?-catenin signaling. 124 plasma and 128
urine metabolites were identified and 40 metabolites were significantly altered
in both plasma and urine. Plasma concentration and urine excretion of 25
metabolites were distinctly different between CKD and controls. They were related
to amino acid, methylamine, purine and lipid metabolisms. Logistic regression
identified four plasma and five urine metabolites. Parts of them were good
correlated with eGFR or serum creatinine. 5-Methoxytryptophan and homocystine and
citrulline were good correlated with both eGFR and creatinine. Clinical factors
were incorporated to establish predictive models. The enhanced metabolite model
showed 5-methoxytryptophan, homocystine and citrulline have satisfactory
accuracy, sensitivity and specificity for predictive CKD. The dysregulation of
CKD was related to amino acid, methylamine, purine and lipid metabolisms.
5-methoxytryptophan, homocystine and citrulline could be considered as additional
GFR-associated biomarker candidates and for indicating advanced renal injury. CKD
caused dysregulation of the plasma and urine metabolome, activation of
inflammatory/oxidative pathway and Wnt/?-catenin signaling and suppression of
antioxidant pathway.
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