晚期慢性肾脏病中表型与脂肪酸代谢之间的联系。
The link between phenotype and fatty acid metabolism in advanced chronic kidney disease.
机构信息
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, Irvine, CA, USA.
出版信息
Nephrol Dial Transplant. 2017 Jul 1;32(7):1154-1166. doi: 10.1093/ndt/gfw415.
BACKGROUND
The kidney plays a central role in elimination of metabolic waste products and regulation of low-molecular weight metabolites via glomerular filtration, tubular secretion and reabsorption. Disruption of these processes results in profound changes in the biochemical milieu of the body fluids, which contribute to complications of chronic kidney disease (CKD) by inducing cytotoxicity and inflammation. Insight into the changes of the composition of metabolites and dysregulation of target genes and proteins enhances the understanding of the pathophysiology of CKD and its complications, and the development of novel therapeutic strategies. Chronic interstitial nephropathy is a common cause of CKD. The present study was designed to determine the effect of chronic interstitial nephropathy on the composition of serum metabolites and regulation of oxidative, inflammatory, fibrotic and cytoprotective pathways.
METHODS
Male Sprague-Dawley rats were randomized to the CKD and control groups ( n = 8/group). CKD was induced by administration of adenine (200 mg/kg body weight/day) by oral gavage for 3 weeks. The control group was treated with the vehicle alone. The animals were then observed for an additional 3 weeks, at which point they were sacrificed and kidney and serum samples were collected. Serum metabolomic and lipidomic analyses were performed using ultra-performance liquid chromatography-quadrupole time-of-flight high-definition mass spectrometry. Kidney tissues were processed for histological and molecular biochemical analyses.
RESULTS
CKD rats exhibited increased plasma urea and creatinine concentrations, renal interstitial fibrosis, tubular damage and up-regulation of pro-inflammatory, pro-oxidant and pro-fibrotic pathways. Comparison of serum from CKD and control rats revealed significant differences in concentrations of amino acids and lipids including 33 metabolites and 35 lipid species. This was associated with marked abnormalities of fatty acid oxidation, and γ-linolenic acid and linoleic acid metabolism in CKD rats. Logistic regression analysis identified tetracosanoic acid, docosatrienoic acid, PC(18:3/14:1) and l -aspartic acid, tetracosanoic acid and docosatrienoic acid as novel biomarkers of chronic interstitial nephropathy.
CONCLUSIONS
Advanced CKD in rats with adenine-induced chronic interstitial nephropathy results in profound changes in the serum metabolome, activation of inflammatory, oxidative and fibrotic pathways, and suppression of cytoprotective and antioxidant pathways.
背景
肾脏通过肾小球滤过、肾小管分泌和重吸收作用，在清除代谢废物和调节低分子量代谢物方面发挥着核心作用。这些过程的破坏会导致体液生化环境发生深刻变化，通过诱导细胞毒性和炎症，导致慢性肾脏病（CKD）的并发症。深入了解代谢物组成的变化以及靶基因和蛋白质的失调，可增强对 CKD 及其并发症的病理生理学的理解，并开发新的治疗策略。慢性间质性肾炎是 CKD 的常见病因。本研究旨在确定慢性间质性肾炎对血清代谢物组成和氧化、炎症、纤维化和细胞保护途径调节的影响。
方法
雄性 Sprague-Dawley 大鼠随机分为 CKD 组和对照组（每组 8 只）。通过口服灌胃给予腺嘌呤（200mg/kg 体重/天）3 周诱导 CKD。对照组给予载体单独处理。然后观察动物 3 周，此时处死并收集肾脏和血清样本。使用超高效液相色谱-四极杆飞行时间高分辨率质谱法进行血清代谢组学和脂质组学分析。处理肾组织进行组织学和分子生化分析。
结果
CKD 大鼠表现出血浆尿素和肌酐浓度升高、肾间质纤维化、肾小管损伤和促炎、促氧化和促纤维化途径上调。CKD 大鼠和对照组大鼠的血清比较显示，氨基酸和脂质浓度存在显著差异，包括 33 种代谢物和 35 种脂质。这与 CKD 大鼠脂肪酸氧化、γ-亚麻酸和亚油酸代谢的明显异常有关。逻辑回归分析确定二十四烷酸、二十二碳三烯酸、PC（18:3/14:1）和 l-天冬氨酸、二十四烷酸和二十二碳三烯酸是慢性间质性肾炎的新型生物标志物。
结论
腺嘌呤诱导的慢性间质性肾炎致大鼠 CKD 晚期，导致血清代谢组发生深刻变化，炎症、氧化和纤维化途径被激活，细胞保护和抗氧化途径被抑制。
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