Adenine-induced chronic kidney and cardiovascular damage in rats
Adenine-induced chronic kidney and cardiovascular damage in rats
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DOI：
10.1016/j.vascn.2013.05.006
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发表时间：
2013-09-01
影响因子：
1.9
通讯作者：
Brown, Lindsay
中科院分区：
文献类型：
--
作者：
Diwan, Vishal;Mistry, Anand;Brown, Lindsay
背景：人类慢性肾功能衰竭伴发心血管疾病的发生率正在增加。慢性饮食腺嘌呤可导致大鼠肾脏损伤。我们使用这一干预措施来研究并发肾脏和心血管损伤的发展。方法：用0.075%、0.25%、0.5%或0.75%的腺嘌呤喂养雄性Wistar大鼠16周，进行剂量-范围研究。0.075%的腺嘌呤对肾脏的影响很小，而0.5%或0.75%的腺嘌呤会对肾脏造成明显的损害；0.25%的腺嘌呤被选作进一步研究，因为它会造成中度的肾脏和心血管损害。在喂养0.25%腺嘌呤的大鼠中，测量了肾功能(血尿素氮(BUN)、血肌酐及其清除；血浆尿酸；蛋白尿)；肾脏结构(胶原、细胞凋亡、炎症、肾小球病变)；以及氧化应激(HO-1)、纤维化(转化生长因子-β、α-SMA)和炎症标志物(肿瘤坏死因子-α、核因子-kappa B p52、核因子-kappa B p50、聚乳酸(2)和ED1)的蛋白表达，以及心血管参数(血压、左心室僵硬、血管反应)。给予别嘌醇(25 mg/kg/天，最后8周)以确定尿酸的作用。结果：0.25%腺嘌呤饮食诱导的16周人慢性肾脏病的特征包括：血尿素氮升高(0.25%腺嘌呤56.5+/-5.4*；对照组6.2+/-0.6 mmol/L；*=p<；0.05)和血肌酐(0.25%腺嘌呤268+/-23*；对照组41.9+/-2.8mU/L)，降低尿素氮和肌酐清除率；蛋白尿；慢性炎症增加，如巨噬细胞和肌成纤维细胞浸润，胶原沉积增加，肾小管萎缩，细胞凋亡，肿瘤坏死因子-α和转化生长因子-β表达；肾小球病变表现为足细胞结蛋白表达增加；HO-1表达增加；血浆尿酸增加。心血管改变包括增加的心室纤维化，收缩压和左心室僵硬，以及受损的血管反应。别嘌醇可降低血尿酸浓度，逆转腺嘌呤引起的肾脏和心血管改变。结论：0.25%腺嘌呤可致大鼠慢性肾脏和心血管疾病。尿酸的产生增加是最有可能的原因，因为别嘌醇减轻了这种损害。(C)2013 Elsevier Inc.保留所有权利。
Background: The incidence of human chronic kidney failure with associated cardiovascular disease is increasing. Kidney damage can be induced in rats by chronic dietary adenine intake. We have used this intervention to investigate the development of concurrent kidney and cardiovascular injury. Methods: Dose-ranging studies were undertaken on male Wistar rats by feeding with adenine (0.075%, 0.25%, 0.5% or 0.75%) for up to 16 weeks. 0.075% adenine produced minimal changes while 0.5% or 0.75% adenine produced marked kidney damage; 0.25% adenine was chosen for further studies since it produced moderate kidney and cardiovascular damage. In rats fed 0.25% adenine, renal function (blood urea nitrogen (BUN), plasma creatinine, and their clearances; plasma uric acid; proteinuria); renal structure (collagen, apoptosis, inflammation, glomerulopathy); and protein expression of markers for oxidative stress (HO-1), fibrosis (TGF-beta, alpha-SMA) and inflammation (TNF-alpha, NF-kappa B p52, NF-kappa B p50, PLA(2) and ED1) were measured, along with cardiovascular parameters (blood pressure, left ventricular stiffness, vascular responses). Allopurinol (25 mg/kg/day, final 8 weeks only) was administered to determine the role of uric acid. Results: 0.25% adenine diet induced characteristics of human chronic kidney disease at 16 weeks including increased BUN (0.25% adenine 56.5 +/- 5.4*; control 6.2 +/- 0.6 mmol/L; * = p < 0.05) and plasma creatinine (0.25% adenine 268 +/- 23*; control 41.9 +/- 2.8 mu g/L), decreased BUN and creatinine clearances; proteinuria; increased chronic inflammation as macrophage and myofibroblast infiltration, increased collagen deposition, tubular atrophy, apoptosis, and TNF-alpha and TGF-beta expression; glomerulopathy as increased podocyte desmin expression; increased HO-1 expression; and increased plasma uric acid. Cardiovascular changes included increased ventricular fibrosis, systolic blood pressure and left ventricular stiffness, and impaired vascular responses. Allopurinol decreased plasma uric acid concentrations and reversed the adenine-induced kidney and cardiovascular changes. Conclusion: Administration of 0.25% adenine to rats induced chronic kidney and cardiovascular disease. Increased uric acid production is the most likely cause since allopurinol attenuated this damage. (C) 2013 Elsevier Inc. All rights reserved.