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Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2317-2332. doi: 10.1016/j.bbadis.2019.05.010. Epub 2019 May 16.

Activated NF-κB/Nrf2 and Wnt/β-catenin pathways are associated with lipid metabolism in CKD patients with microalbuminuria and macroalbuminuria.

Author information

1
School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.
2
Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, 1001 Health Sciences Rd, Irvine, CA 92897, USA.
3
Department of Nephrology, Baoji Central Hospital, No. 8 Jiangtan Road, Baoji, Shaanxi 721008, China.
4
Department of Nephrology, Shaanxi Traditional Chinese Medicine Hospital, No. 2 Xihuamen, Xi'an, Shaanxi 710003, China.
5
Department of Nephrology, Xi'an No. 4 Hospital, No. 21 Jiefang Road, Xi'an 710004, China.
6
School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China; Department of Internal Medicine, University of New Mexico, Comprehensive Cancer Center, Albuquerque, NM 87131, USA.
7
School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China. Electronic address: zyy@nwu.edu.cn.

Abstract

Early diagnosis of CKD patients at risk for microalbuminuria or macroalbuminuria could facilitate clinical outcomes and long-term survival. Considering the few and limited efficacy of current biomarkers in early detection, we aim to discover plasma lipids that effectively predict the development of CKD paitents with microalbuminuria or macroalbuminuria. A total of 380 healthy controls and 1156 patients with CKD stages 3 to 5 were stratified by urine albumin-creatinine ratio as microalbuminuria (30-300 mg/g) and macroalbuminuria (>300 mg/g). Fasting plasma samples were determined by UPLC-HDMS based on lipidomics. Quantitative real-time polymerase chain reaction, Western blot and immunohistochemical analyses were used to validate the lipid metabolism-associated pathways. Pathway analysis demonstrated that these lipids were closely associated with PPARγ, inflammatory mediator regulation of TRP channels and RAS signaling, which were intimately involved in activated NF-κB and Nrf2 pathways. We further carried out pathway validation and demonstrated that NF-κB pathway was activated in patients with macroalbuminuria compared with CKD patients with microalbuminuria, while Nrf2-associated protein expression was downregulated, which was accompanied by the up-regulation of Wnt/β-catenin signaling pathway. Four lipids including DTA, 5,8-TDA, GGD3 and DHA that showed great potential in the discrimination of CKD patients with microalbuminuria and healthy controls were selected by logistic regression analysis. Additionally, six lipid species including CDCA, glucosylceramide, GGD2, TTA, DHA and EDA that contributed to the discrimination of CKD patients with microalbuminuria and macroalbuminuria were selected by logistic LASSO regression Gangliosides were first identified and might be promising therapeutic targets for CKD patients with the different degree of albuminuria. Collectively, this study first demonstrates the association of plasma inflammation, oxidative stress, Wnt/β-catenin and lipid metabolism in CKD patients with microalbuminuria and macroalbuminuria.

KEYWORDS:

Chronic kidney disease; Inflammation; Lipid biomarker; Lipidomics; Macroalbuminuria; Microalbuminuria

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