激活的 NF-κB/Nrf2 和 Wnt/β-连环蛋白通路与伴有微量白蛋白尿和大量白蛋白尿的 CKD 患者的脂质代谢有关。

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

机构信息

School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.

Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, 1001 Health Sciences Rd, Irvine, CA 92897, USA.

出版信息

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.

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.

摘要

早期诊断有微量白蛋白尿或大量白蛋白尿风险的 CKD 患者有助于改善临床结局和长期生存率。考虑到目前生物标志物在早期检测中的数量有限和效果有限,我们旨在发现能够有效预测有微量白蛋白尿或大量白蛋白尿的 CKD 患者发展情况的血浆脂质。共有 380 名健康对照者和 1156 名 CKD 3 至 5 期患者按尿白蛋白与肌酐比值分层为微量白蛋白尿(30-300mg/g)和大量白蛋白尿(>300mg/g)。采用基于脂质组学的 UPLC-HDMS 测定空腹血浆样本。采用定量实时聚合酶链反应、Western blot 和免疫组织化学分析验证脂质代谢相关途径。途径分析表明,这些脂质与 PPARγ、TRP 通道炎症介质调节和 RAS 信号密切相关,而这些途径与激活的 NF-κB 和 Nrf2 途径密切相关。我们进一步进行了途径验证,并表明与有微量白蛋白尿的 CKD 患者相比,大量白蛋白尿患者的 NF-κB 途径被激活,而 Nrf2 相关蛋白表达下调,同时 Wnt/β-catenin 信号通路被上调。通过逻辑回归分析,选择了在区分有微量白蛋白尿的 CKD 患者和健康对照者方面具有巨大潜力的 4 种脂质,包括 DTA、5,8-TDA、GGD3 和 DHA。此外,通过逻辑 LASSO 回归选择了 6 种脂质,包括 CDCA、神经酰胺葡萄糖苷、GGD2、TTA、DHA 和 EDA,它们有助于区分有微量白蛋白尿和大量白蛋白尿的 CKD 患者。神经节苷脂是首次被鉴定出来的,它们可能是不同程度白蛋白尿的 CKD 患者的有前途的治疗靶点。总的来说,这项研究首次证明了 CKD 有微量白蛋白尿和大量白蛋白尿患者的血浆炎症、氧化应激、Wnt/β-catenin 和脂质代谢之间的关联。

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