Ge Shuwang, Hertel Barbara, Koltsova Ekaterina K, Sörensen-Zender Inga, Kielstein Jan T, Ley Klaus, Haller Hermann, von Vietinghoff Sibylle
From the Department of Medicine, Hannover Medical School, Hannover, Germany.
Circ Res. 2013 Sep 27;113(8):965-74. doi: 10.1161/CIRCRESAHA.113.301934. Epub 2013 Aug 1.
Atherosclerosis is a major cause of death in patients with chronic kidney disease. Chronic inflammation of the arterial wall including invasion, proliferation, and differentiation of leukocytes is important in atherosclerotic lesion development. How atherosclerotic inflammation is altered in renal impairment is incompletely understood.
This study analyzed leukocytes of the atherosclerotic aorta in mice with impaired and normal renal function and studied a mechanism for the alteration in aortic myeloid leukocytes.
Unilateral nephrectomy significantly decreased glomerular filtration rate and increased atherosclerotic lesion size and aortic leukocyte numbers in 2 murine atherosclerosis models, apolipoprotein E (Apoe(-/-)) and low-density lipoprotein (LDL) receptor-deficient (LDLr(-/-)) mice. The number of aortic myeloid cells increased significantly. They took-up less oxidized LDL, whereas CD11c expression, interaction with T cells, and aortic T cell proliferation were significantly enhanced in renal impairment. In human peripheral blood mononuclear cell cultures, chronic kidney disease serum decreased lipid uptake and increased human leukocyte antigen II (HLA II) expression. Supplementation with interleukin-17A similarly increased HLA II and CD11c expression and impaired oxidized LDL uptake. Interleukin-17A expression was increased in atherosclerotic mice with renal impairment. Ablation of interleukin-17A in LDLr(-/-) mice by lethal irradiation and reconstitution with Il17a(-/-) bone marrow abolished the effect of renal impairment on aortic CD11b(+) myeloid cell accumulation, CD11c expression, and cell proliferation. Atherosclerotic lesion size was decreased to levels observed in normal kidney function.
Kidney function modifies arterial myeloid cell accumulation and phenotype in atherosclerosis. Our results suggest a central role for interleukin-17A in aggravation of vascular inflammation and atherosclerosis in renal impairment.
动脉粥样硬化是慢性肾脏病患者死亡的主要原因。动脉壁的慢性炎症，包括白细胞的浸润、增殖和分化，在动脉粥样硬化病变发展中起重要作用。肾功能损害时动脉粥样硬化炎症如何改变尚不完全清楚。
本研究分析了肾功能受损和正常小鼠动脉粥样硬化主动脉中的白细胞，并研究了主动脉髓样白细胞改变的机制。
在两种小鼠动脉粥样硬化模型，即载脂蛋白E（Apoe(-/-)）和低密度脂蛋白（LDL）受体缺陷（LDLr(-/-)）小鼠中，单侧肾切除显著降低了肾小球滤过率，增加了动脉粥样硬化病变大小和主动脉白细胞数量。主动脉髓样细胞数量显著增加。它们摄取的氧化型低密度脂蛋白较少，而在肾功能损害时，CD11c表达、与T细胞的相互作用以及主动脉T细胞增殖均显著增强。在人外周血单核细胞培养中，慢性肾脏病血清降低了脂质摄取并增加了人白细胞抗原II（HLA II）表达。补充白细胞介素-17A同样增加了HLA II和CD11c表达，并损害了氧化型低密度脂蛋白摄取。肾功能受损的动脉粥样硬化小鼠中白细胞介素-17A表达增加。通过致死性照射清除LDLr(-/-)小鼠中的白细胞介素-17A并用Il17a(-/-)骨髓进行重建，消除了肾功能损害对主动脉CD11b(+)髓样细胞积聚、CD11c表达和细胞增殖的影响。动脉粥样硬化病变大小降至肾功能正常时观察到的水平。
肾功能在动脉粥样硬化中改变动脉髓样细胞积聚和表型。我们的结果表明白细胞介素-17A在肾功能损害时血管炎症和动脉粥样硬化加重中起核心作用。
