Gene and protein expressions and metabolomics exhibit activated redox signaling and wnt/β-catenin pathway are associated with metabolite dysfunction in patients with chronic kidney disease.
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-κB 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/β-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/β-catenin signaling and suppression of antioxidant pathway.
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.
Dan-Qian
DQ
Chen
Research Center of TCM Processing Technology, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China.
Gang
G
Cao
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.
Hua
H
Chen
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.
Dan
D
Liu
Department of Nephrology, Baoji Central Hospital, No. 8 Jiangtan Road, Baoji, Shaanxi 721008, China.
Wei
W
Su
Department of Nephrology, Affiliated Hospital of Shaanxi Institute of Traditional Chinese Medicine, No. 2 Xihuamen, Xi'an, Shaanxi 710003, China.
Xiao-Yong
XY
Yu
Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, MedSci 1 C352, Irvine, CA 92897, USA.
Nosratola D
ND
Vaziri
School of Pharmacy, Henan University, Kaifeng, No. 85 Minglun Road, Henan 475004, China.
Xiu-Hua
XH
Liu
Solution Centre, Waters Technologies (Shanghai) Ltd., No. 1000 Jinhai Road, Shanghai 201203, China.
Xu
X
Bai
Department of Nephrology, Xi'an No. 4 Hospital, No. 21 Jiefang Road, Xi'an 710004, China.
Li
L
Zhang
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China. Electronic address: zyy@nwu.edu.cn.
Ying-Yong
YY
Zhao
D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D010084:Oxidation-Reduction; D010949:Plasma / Q000737:chemistry; D040901:Proteomics / Q000379:methods*; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D014556:Urine / Q000737:chemistry; D060449:Wnt Signaling Pathway
D000975:Antioxidants
Chronic kidney disease; Clinical factors; Inflammation; Metabolomics; Oxidative stress; Wnt/beta-catenin signaling