Cho Eunjung, Kim Mina, Ko Yoon Sook, Lee Hee Young, Song Myeongjin, Kim Myung Gyu, Kim Hyoung-Kyu, Cho Won-Yong, Jo Sang-Kyung
Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Korea University Anam Hospital, Seoul, South Korea.
Nephrol Dial Transplant. 2013 Nov;28(11):2766-78. doi: 10.1093/ndt/gft376. Epub 2013 Sep 5.
Cardiorenal syndrome is now frequently recognized, and the combined dysfunction of heart and kidney increases morbidity and mortality. This study aimed to investigate possible mechanisms that underlie renal damage following heart dysfunction using a rat myocardial infarction model, focusing on the inflammatory pathway.
Rats were randomized into four groups: normal, volume depletion, sham operation and myocardial infarction (MI). MI was induced by the ligation of the left coronary artery and a volume depletion model was produced by low-salt diet and furosemide injection. Biochemical, histological and flow cytometric analyses were performed at 3 days and 4 and 8 weeks after MI.
On Day 3 following MI, the development of subclinical acute kidney injury was identified through significantly increased serum and urine neutrophil gelatinase-associated lipocalin level. We detected the increase of activated monocytes (CC chemokine receptor 2(+) ED-1(+)) in peripheral blood, along with the infiltration of ED-1(+) macrophages and the increment of nuclear p65 in the kidney of MI rats, suggesting the contribution of nuclear factor-kappa B-mediated inflammation in the development of Type 1 cardiorenal syndrome (CRS). The inflammatory cytokines, interleukin-6 and tumour necrosis factor-α (TNF-α) mRNA expression, as well as microvascular endothelial permeability and tubular cell apoptosis, significantly increased in the kidneys of MI rats. At 4 and 8 weeks after MI, tubular cell apoptosis, ED-1(+) macrophage infiltration and interstitial fibrosis increased in MI rats, and these chronic changes were significantly mitigated by systemic monocyte/macrophage depletion using liposome clodronate.
This study identifies the possible important role of inflammatory response as a mediator of heart-kidney crosstalk in CRS.
心肾综合征目前已被频繁认识到，心脏和肾脏的联合功能障碍会增加发病率和死亡率。本研究旨在使用大鼠心肌梗死模型，以炎症途径为重点，探讨心脏功能障碍后肾脏损伤的潜在机制。
将大鼠随机分为四组：正常组、容量耗竭组、假手术组和心肌梗死组（MI）。通过结扎左冠状动脉诱导心肌梗死，通过低盐饮食和注射呋塞米建立容量耗竭模型。在心肌梗死后3天、4周和8周进行生化、组织学和流式细胞术分析。
在心肌梗死后第3天，通过血清和尿液中性粒细胞明胶酶相关脂质运载蛋白水平显著升高，确定了亚临床急性肾损伤的发生。我们检测到外周血中活化单核细胞（CC趋化因子受体2(+) ED-1(+)）增加，同时MI大鼠肾脏中ED-1(+)巨噬细胞浸润和核p65增加，提示核因子-κB介导的炎症在1型心肾综合征（CRS）发展中的作用。MI大鼠肾脏中炎性细胞因子、白细胞介素-6和肿瘤坏死因子-α（TNF-α）mRNA表达，以及微血管内皮通透性和肾小管细胞凋亡显著增加。在心肌梗死后4周和8周，MI大鼠肾小管细胞凋亡、ED-1(+)巨噬细胞浸润和间质纤维化增加，使用氯膦酸脂质体进行全身单核细胞/巨噬细胞清除可显著减轻这些慢性变化。
本研究确定了炎症反应作为CRS中心脏-肾脏相互作用介质的可能重要作用。
