Data_Sheet_1_Paradoxical reduction of plasma lipids and atherosclerosis in mice with adenine-induced chronic kidney disease and hypercholesterolemia.pdf

BackgroundAtherosclerotic cardiovascular disease is prevalent among patients with chronic kidney disease (CKD). In this study, we initially aimed to test whether vascular calcification associated with CKD can worsen atherosclerosis. However, a paradoxical finding emerged from attempting to test this hypothesis in a mouse model of adenine-induced CKD.
MethodsWe combined adenine-induced CKD and diet-induced atherosclerosis in mice with a mutation in the low-density lipoprotein receptor gene. In the first study, mice were co-treated with 0.2% adenine in a western diet for 8 weeks to induce CKD and atherosclerosis simultaneously. In the second study, mice were pre-treated with adenine in a regular diet for 8 weeks, followed by a western diet for another 8 weeks.
ResultsCo-treatment with adenine and a western diet resulted in a reduction of plasma triglycerides and cholesterol, liver lipid contents, and atherosclerosis in co-treated mice when compared with the western-only group, despite a fully penetrant CKD phenotype developed in response to adenine. In the two-step model, renal tubulointerstitial damage and polyuria persisted after the discontinuation of adenine in the adenine-pre-treated mice. The mice, however, had similar plasma triglycerides, cholesterol, liver lipid contents, and aortic root atherosclerosis after being fed a western diet, irrespective of adenine pre-treatment. Unexpectedly, adenine pre-treated mice consumed twice the calories from the diet as those not pre-treated without showing an increase in body weight.
ConclusionThe adenine-induced CKD model does not recapitulate accelerated atherosclerosis, limiting its use in pre-clinical studies. The results indicate that excessive adenine intake impacts lipid metabolism.

背景：动脉粥样硬化性心血管疾病在慢性肾脏病（CKD，chronic kidney disease）患者中高发。本研究最初旨在验证与慢性肾脏病相关的血管钙化是否会加重动脉粥样硬化。然而，在腺嘌呤诱导的慢性肾脏病小鼠模型中验证该假说时，却得到了自相矛盾的实验结果。

方法：本研究将腺嘌呤诱导的慢性肾脏病与饮食诱导的动脉粥样硬化相结合，采用低密度脂蛋白受体基因发生突变的小鼠作为实验对象。第一项实验中，小鼠同时喂食含0.2%腺嘌呤的西式饮食，持续8周，以同步诱导慢性肾脏病与动脉粥样硬化。第二项实验中，小鼠先以普通饮食搭配腺嘌呤预处理8周，随后更换为西式饮食继续饲养8周。

结果：与仅喂食西式饮食的对照组相比，同时给予腺嘌呤与西式饮食的小鼠，其血浆甘油三酯、胆固醇水平，肝脏脂质含量以及动脉粥样硬化病变程度均有所降低，尽管腺嘌呤成功诱导出了完全表型的慢性肾脏病。在两步造模模型中，腺嘌呤预处理小鼠在停止腺嘌呤摄入后，肾小管间质损伤与多尿症状仍持续存在。但在更换西式饮食饲养后，无论是否经过腺嘌呤预处理，小鼠的血浆甘油三酯、胆固醇水平、肝脏脂质含量以及主动脉根部动脉粥样硬化程度均无显著差异。出乎意料的是，腺嘌呤预处理小鼠的饮食热量摄入为未预处理小鼠的两倍，但体重并未出现相应增长。

结论：腺嘌呤诱导的慢性肾脏病模型无法重现加速型动脉粥样硬化表型，限制了其在临床前研究中的应用。本研究结果提示，过量腺嘌呤摄入会对脂质代谢产生影响。