Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice

Chronic kidney disease (CKD) leads to uremia. CKD is characterized by a gradual increase in kidney fibrosis and loss of kidney function, which is associated with a progressive increase in risk of atherosclerosis and cardiovascular death. To prevent progression of both kidney fibrosis and atherosclerosis in uremic settings, insight into new treatment options with effects on both parameters is warranted. The GLP-1 analogue liraglutide improves glucose homeostasis, and is approved for treatment of type 2 diabetes. Animal studies suggest that GLP-1 also dampens inflammation and atherosclerosis. Our aim was to examine effects of liraglutide on kidney fibrosis and atherosclerosis in a mouse model of moderate uremia (5/6 nephrectomy (NX)). Uremic (n = 29) and sham-operated (n = 14) atherosclerosis-prone low density lipoprotein receptor knockout mice were treated with liraglutide (1000 μg/kg, s.c. once daily) or vehicle for 13 weeks. As expected, uremia increased aortic atherosclerosis. In the remnant kidneys from NX mice, flow cytometry revealed an increase in the number of monocyte-like cells (CD68+F4/80-), CD4+, and CD8+ T-cells, suggesting that moderate uremia induced kidney inflammation. Furthermore, markers of fibrosis (i.e. Col1a1 and Col3a1) were upregulated, and histological examinations showed increased glomerular diameter in NX mice. Importantly, liraglutide treatment attenuated atherosclerosis (~40%, p

慢性肾脏病（CKD）可导致尿毒症。CKD以肾纤维化进行性加重、肾功能逐步丧失为特征，且与动脉粥样硬化风险及心血管死亡风险的渐进性升高密切相关。为在尿毒症状态下同时延缓肾纤维化与动脉粥样硬化的进展，亟需探索可同时调控这两类病理进程的新型治疗策略。胰高血糖素样肽-1（GLP-1）类似物利拉鲁肽可改善血糖稳态，目前已获批用于2型糖尿病的临床治疗。既往动物实验研究表明，GLP-1还可抑制炎症反应并延缓动脉粥样硬化的进展。本研究旨在探讨利拉鲁肽对中度尿毒症（5/6肾切除（NX））小鼠模型中肾纤维化与动脉粥样硬化的干预效应。我们将动脉粥样硬化易感型低密度脂蛋白受体敲除小鼠分为尿毒症造模组（n = 29）与假手术组（n = 14），分别予以利拉鲁肽（1000 μg/kg，s.c. 每日一次）或溶媒对照，连续治疗13周。正如预期，尿毒症造模显著增加了小鼠的主动脉粥样硬化病变负荷。对5/6肾切除小鼠的残肾组织进行流式细胞术检测后发现，单核细胞样细胞（CD68+F4/80-）、CD4阳性T细胞及CD8阳性T细胞的数量均显著升高，提示中度尿毒症可诱发肾脏炎症反应。此外，肾纤维化标志物（即Col1a1与Col3a1）的表达水平显著上调，组织病理学检查亦显示5/6肾切除小鼠的肾小球直径明显增加。值得注意的是，利拉鲁肽治疗可缓解动脉粥样硬化病变（约40%，p