CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice.
CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice.
复制标题
DOI：
10.1152/ajprenal.00316.2013
复制
发表时间：
2013-11
期刊：
影响因子：
--
通讯作者：
T. Sullivan;Z. Miao;D. Dairaghi;A. Krasiński;Yu Wang;Bin N. Zhao;T. Baumgart;L. Ertl;A. Pennell;L. Seitz;J. Powers;Ru-tong Zhao;S. Ungashe;Zheng Wei;L. Boring;C. Tsou;I. Charo;R. Berahovich;T. Schall;J. Jaén
中科院分区：
文献类型：
--
作者：
T. Sullivan;Z. Miao;D. Dairaghi;A. Krasiński;Yu Wang;Bin N. Zhao;T. Baumgart;L. Ertl;A. Pennell;L. Seitz;J. Powers;Ru-tong Zhao;S. Ungashe;Zheng Wei;L. Boring;C. Tsou;I. Charo;R. Berahovich;T. Schall;J. Jaén
趋化因子（C-C基序）受体2（CCR 2）是单核细胞迁移到炎症组织的中心。新型CCR 2拮抗剂CCX 140-B目前正处于糖尿病肾病的两项独立的2期临床试验中，最近已显示可降低2型糖尿病患者的血红蛋白A1 c和空腹血糖水平。在本报告中，我们描述了该化合物对糖尿病小鼠血糖和肾功能参数的影响。由于CCX 140-B对小鼠CCR 2具有低亲和力，因此产生转基因人CCR 2敲入小鼠，并通过高脂肪饮食（饮食诱导的肥胖）或通过缺失瘦素受体基因（db/db）使其患糖尿病。CCX 140-B治疗在两种模型中均导致白蛋白尿减少，这与肾小球肥大减少和足细胞密度增加相关。此外，用CCX 140-B治疗饮食诱导的肥胖小鼠导致空腹血糖和胰岛素水平降低，胰岛素抵抗值的稳态模型评估正常化，以及脂肪组织炎性巨噬细胞数量减少。与其他CCR 2拮抗剂不同，CCX 140-B对CCR 2配体CCL 2的血浆水平或血液单核细胞的数量没有影响。这些结果支持在肾功能受损的糖尿病受试者中持续评价该分子。
Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2 knockin mice were generated and rendered diabetic with either a high-fat diet (diet-induced obesity) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of diet-induced obese mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessment of insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function.