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Open Access Publications from the University of California

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

  • Author(s): Feng, Ya-Long
  • Chen, Hua
  • Chen, Dan-Qian
  • Vaziri, Nosratola D
  • Su, Wei
  • Ma, Shi-Xing
  • Shang, You-Quan
  • Mao, Jia-Rong
  • Yu, Xiao-Yong
  • Zhang, Li
  • Guo, Yan
  • Zhao, Ying-Yong
  • et al.

Early detection of CKD patients at risk for micro- or macroalbuminuria facilitates prevention and treatment. We aimed to discover plasma lipids that predict the development of micro- 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-lipidomics. Quantitative real-time RT-PCR, Western blot and immunohistochemical analyses were used for validating the lipid metabolism-associated pathway. Pathway analysis demonstrated that these lipids are associated with PPARγ, inflammatory mediator regulation of TRP channels and RAS signaling, which consistent with activated NF-κB and Nrf2 pathways. Pathway validation demonstrated that macroalbuminuria patients showed activation of NF-κB and up-regulation of inflammatory and oxidant mRNA and protein expression and down-regulation of Nrf2-associated anti-oxidant gene mRNA and protein expression, accompanied by activated Wnt/β-catenin signaling pathway compared to microalbuminuria patients. Four lipids DTA, 5,8-TDA, GGD3 and DHA is selected by logistic regression analysis and they robustly distinguished microalbuminuria patients from healthy controls with high sensitivity and specificity. Six lipid species CDCA, glucosylceramide, GGD2, TTA, DHA and EDA is selected by logistic lasso regression and they discriminate between CKD patients with microalbuminuria and macroalbuminuria. Gangliosides are first identified and they might be considered as therapeutic targets for CKD patients with the different degree of albuminuria. This study first demonstrates the association of plasma inflammation, oxidative stress, Wnt/β-catenin and lipid metabolism in CKD patients with microalbuminuria and macroalbuminuria.

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