Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury
Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury
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DOI：
10.1152/ajprenal.00332.2011
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发表时间：
2011-12-01
影响因子：
4.2
通讯作者：
Okusa, Mark D.
中科院分区：
文献类型：
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作者：
Awad, Alaa S.;Kinsey, Gilbert R.;Okusa, Mark D.
Awad AS、Kinsey GR、Khutsishvili K、Gao T、Bolton WK、Okusa MD。单核细胞/巨噬细胞趋化因子受体 CCR2 介导糖尿病肾损伤。 Am J Physiol Renal Physiol 301：F1358-F1366，2011。首次发表于 2011 年 8 月 31 日； doi:10.1152/ajprenal.00332.2011.-单核细胞/巨噬细胞募集与糖尿病肾病 (DN) 肾损伤的进展密切相关。 C-C 趋化因子受体 (CCR) 2 调节单核细胞/巨噬细胞向受损组织的迁移。然而，CCR2 介导的单核细胞/巨噬细胞募集在糖尿病肾病中的直接作用仍不清楚。我们报告说，药物阻断或 CCR2 遗传缺陷可在 Ins2（秋田）和链脲佐菌素 (STZ) 诱导的糖尿病肾病中提供肾脏保护。与媒介物相比，在 Ins2（秋田）小鼠中使用选择性 CCR2 拮抗剂 RS504393 阻断 CCR2 12 周，可显着减弱蛋白尿、血液尿素氮和血浆肌酐的增加、组织学变化以及肾小球巨噬细胞的募集。此外，尽管血糖水平相当，但与 CCR2(+/+) 小鼠相比，缺乏 CCR2 (CCR2(-/-)) 的小鼠通过减少蛋白尿并表现出较少的纤连蛋白 mRNA 表达和炎性细胞因子产生来模仿 CCR2 阻断。来自 CCR2(+/+) 或 CCR2(-/-) 小鼠的骨髓来源的单核细胞过继转移到 CCR2(-/-) 小鼠体内，通过尿白蛋白排泄增加和肾脏巨噬细胞招募来评估，逆转了糖尿病 CCR2(-/-) 小鼠的肾组织保护作用，表明单核细胞从循环迁移到肾脏不需要 CCR2 糖尿病肾病。这些发现提供了证据表明 CCR2 对于单核细胞/巨噬细胞诱导的糖尿病肾损伤是必需的，并表明阻断 CCR2 可能是治疗 DN 的一种新的治疗方法。
Awad AS, Kinsey GR, Khutsishvili K, Gao T, Bolton WK, Okusa MD. Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury. Am J Physiol Renal Physiol 301: F1358-F1366, 2011. First published August 31, 2011; doi:10.1152/ajprenal.00332.2011.-Monocyte/macrophage recruitment correlates strongly with the progression of renal impairment in diabetic nephropathy (DN). C-C chemokine receptor (CCR) 2 regulates monocyte/macrophage migration into injured tissues. However, the direct role of CCR2-mediated monocyte/macrophage recruitment in diabetic kidney disease remains unclear. We report that pharmacological blockade or genetic deficiency of CCR2 confers kidney protection in Ins2(Akita) and streptozotocin (STZ)-induced diabetic kidney disease. Blocking CCR2 using the selective CCR2 antagonist RS504393 for 12 wk in Ins2(Akita) mice significantly attenuated albuminuria, the increase in blood urea nitrogen and plasma creatinine, histological changes, and glomerular macrophage recruitment compared with vehicle. Furthermore, mice lacking CCR2 (CCR2(-/-)) mimicked CCR2 blockade by reducing albuminuria and displaying less fibronectin mRNA expression and inflammatory cytokine production compared with CCR2(+/+) mice, despite comparable blood glucose levels. Bone marrow-derived monocytes from CCR2(+/+) or CCR2(-/-) mice adoptively transferred into CCR2(-/-) mice reversed the renal tissue-protective effect in diabetic CCR2(-/-) mice as evaluated by increased urinary albumin excretion and kidney macrophage recruitment, indicating that CCR2 is not required for monocyte migration from the circulation into diabetic kidneys. These findings provide evidence that CCR2 is necessary for monocyte/macrophage-induced diabetic renal injury and suggest that blocking CCR2 could be a novel therapeutic approach in the treatment of DN.