Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan;
Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan;
Am J Physiol Renal Physiol. 2014 Sep 1;307(5):F581-92. doi: 10.1152/ajprenal.00670.2013. Epub 2014 Jun 11.
Emerging data have suggested that acute kidney injury (AKI) is often incompletely repaired and can lead to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. However, the underlying mechanisms linking AKI to CKD remain obscure. The present study aimed to investigate the role of cysteine-rich protein 61 (Cyr61) after unilateral kidney ischemia-reperfusion injury (IRI) in mice. After IRI, increased expression of Cyr61 was detected, predominately in the proximal tubular epithelium. This was confirmed by in vitro experiments, which showed that hypoxia stimulated Cyr61 expression in cultured proximal tubular epithelial cells. The proinflammatory property of Cyr61 was indicated by its ability to upregulate monocyte chemoattractant protein-1 and IL-6. Additionally, we found elevated urinary Cyr61 excretion in patients with AKI. Notably, treatment of mice with an anti-Cyr61 antibody attenuated the upregulation of kidney monocyte chemoattractant protein-1, IL-6, IL-1β, and macrophage inflammatory protein-2 and reduced the infiltration of F4/80-positive macrophages on days 7 and 14 after IRI. In addition, blockade of Cyr61 reduced the mRNA expression of collagen, transforming growth factor-β, and plasminogen activator inhibitor-I as well as the degree of collagen fibril accumulation, as evaluated by picrosirius red staining, and levels of α-smooth muscle actin proteins by day 14. Concurrently, in the treated group, peritubular microvascular density was more preserved on day 14. We conclude that Cyr61 blockade inhibits the triad of inflammation, interstitial fibrosis, and capillary rarefaction after severe ischemic AKI. The results of this study expand the knowledge of the mechanisms underlying the AKI-to-CKD transition and suggest that Cyr61 is a potential therapeutic target.
新出现的数据表明，急性肾损伤（AKI）常常不能完全修复，并可能导致慢性肾脏病（CKD），其特征为肾小管间质炎症和纤维化。然而，将 AKI 与 CKD 联系起来的潜在机制仍不清楚。本研究旨在探讨胱氨酸丰富蛋白 61（Cyr61）在单侧肾缺血再灌注损伤（IRI）后在小鼠中的作用。IRI 后，检测到 Cyr61 的表达增加，主要在近端肾小管上皮细胞中。这一点通过体外实验得到了证实，该实验表明缺氧刺激培养的近端肾小管上皮细胞中 Cyr61 的表达。Cyr61 的促炎特性表现为其上调单核细胞趋化蛋白-1 和 IL-6 的能力。此外，我们发现 AKI 患者的尿 Cyr61 排泄量增加。值得注意的是，用抗 Cyr61 抗体治疗小鼠可减弱肾单核细胞趋化蛋白-1、IL-6、IL-1β和巨噬细胞炎症蛋白-2的上调，并减少 IRI 后 7 天和 14 天 F4/80 阳性巨噬细胞的浸润。此外，阻断 Cyr61 可减少胶原、转化生长因子-β和纤溶酶原激活物抑制剂-I 的 mRNA 表达以及胶原纤维积聚的程度，如天狼星红染色评估的以及到第 14 天的α-平滑肌肌动蛋白蛋白水平。同时，在治疗组中，第 14 天肾小管周围微血管密度得到了更好的保留。我们得出结论，Cyr61 阻断抑制严重缺血性 AKI 后炎症、间质纤维化和毛细血管稀疏的三联征。本研究的结果扩展了对 AKI 向 CKD 转化的机制的认识，并表明 Cyr61 是一个潜在的治疗靶点。
