Zheng Shirong, Coventry Susan, Cai Lu, Powell David W, Jala Venkatakrishna R, Haribabu Bodduluri, Epstein Paul N
Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.
Department of Pathology, University of Louisville, Louisville, KY 40202, USA.
J Diabetes Res. 2016;2016:5362506. doi: 10.1155/2016/5362506. Epub 2015 Dec 20.
In diabetic nephropathy (DN) proinflammatory chemokines and leukocyte infiltration correlate with tubulointerstitial injury and declining renal function. The atypical chemokine receptor ACKR2 is a chemokine scavenger receptor which binds and sequesters many inflammatory CC chemokines but does not transduce typical G-protein mediated signaling events. ACKR2 is known to regulate diverse inflammatory diseases but its role in DN has not been tested. In this study, we utilized ACKR2(-/-) mice to test whether ACKR2 elimination alters progression of diabetic kidney disease. Elimination of ACKR2 greatly reduced DN in OVE26 mice, an established DN model. Albuminuria was significantly lower at 2, 4, and 6 months of age. ACKR2 deletion did not affect diabetic blood glucose levels but significantly decreased parameters of renal inflammation including leukocyte infiltration and fibrosis. Activation of pathways that increase inflammatory gene expression was attenuated. Human biopsies stained with ACKR2 antibody revealed increased staining in diabetic kidney, especially in some tubule and interstitial cells. The results demonstrate a significant interaction between diabetes and ACKR2 protein in the kidney. Unexpectedly, ACKR2 deletion reduced renal inflammation in diabetes and the ultimate response was a high degree of protection from diabetic nephropathy.
在糖尿病肾病（DN）中，促炎趋化因子和白细胞浸润与肾小管间质损伤及肾功能下降相关。非典型趋化因子受体ACKR2是一种趋化因子清除受体，它能结合并隔离多种炎性CC趋化因子，但不转导典型的G蛋白介导的信号事件。已知ACKR2可调节多种炎性疾病，但其在糖尿病肾病中的作用尚未得到验证。在本研究中，我们利用ACKR2基因敲除小鼠来测试去除ACKR2是否会改变糖尿病肾病的进展。去除ACKR2可显著减轻OVE26小鼠（一种已建立的糖尿病肾病模型）的糖尿病肾病。在2、4和6月龄时，蛋白尿水平显著降低。ACKR2基因缺失不影响糖尿病小鼠的血糖水平，但可显著降低包括白细胞浸润和纤维化在内的肾脏炎症参数。增加炎性基因表达的信号通路激活减弱。用ACKR2抗体染色的人肾活检组织显示，糖尿病肾病患者肾脏中的染色增加，尤其是在一些肾小管和间质细胞中。结果表明，糖尿病与肾脏中的ACKR2蛋白之间存在显著相互作用。出乎意料的是，ACKR2基因缺失可减轻糖尿病患者的肾脏炎症，最终的反应是对糖尿病肾病具有高度保护作用。
