Podocyte-specific chemokine (C-C motif) receptor 2 overexpression mediates diabetic renal injury in mice.
Podocyte-specific chemokine (C-C motif) receptor 2 overexpression mediates diabetic renal injury in mice.
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DOI：
10.1016/j.kint.2016.09.042
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发表时间：
2017-03
影响因子：
19.6
通讯作者：
Awad AS
中科院分区：
文献类型：
--
作者：
You H;Gao T;Raup-Konsavage WM;Cooper TK;Bronson SK;Reeves WB;Awad AS
炎症是糖尿病和糖尿病肾病的重要病理生理机制。最近，我们发现巨噬细胞直接参与了糖尿病肾损害，而趋化因子(C-C基序)受体2(CCR2)的药物阻断或遗传缺陷在糖尿病肾病中起到了肾脏保护作用。然而，CCR2在糖尿病肾病的足细胞等肾来源细胞中的直接作用仍不清楚。为了研究这一点，我们建立了一种在肾病易感性(DBA/2J)和CCR2缺失(CCR2−/−)背景和CCR2+/−杂合子对照的足细胞(TG(NPHS2-CCR2))特异表达CCR2的转基因小鼠模型。用链脲佐菌素诱发糖尿病。正如预期的那样，在糖尿病九周后，CCR2的缺失赋予了肾脏保护作用。相反，在CCR2−/−小鼠足细胞中过表达CCR2后，在链脲佐菌素诱导的糖尿病9周后，尿蛋白、血尿素氮、组织病理学改变、肾脏纤维连接蛋白和1型胶原表达显著增加，足细胞丢失，肾小球凋亡。有趣的是，在小鼠中，肾脏巨噬细胞募集或炎性细胞因子水平没有同时增加。这些发现支持足细胞中CCR2的表达在糖尿病肾损伤中的直接作用，而不依赖于单核/巨噬细胞的募集。因此，靶向足细胞CCR2信号通路可能是治疗糖尿病肾病的一种新的治疗方法。
Inflammation is a central pathophysiologic mechanism that contributes to diabetes mellitus and diabetic nephropathy. Recently, we showed that macrophages directly contribute to diabetic renal injury, and that pharmacological blockade or genetic deficiency of chemokine (C-C motif) receptor 2 (CCR2) confers kidney protection in diabetic nephropathy. However, the direct role of CCR2 in kidney-derived cells such as podocytes in diabetic nephropathy remains unclear. To study this, we developed a transgenic mouse model expressing CCR2 specifically in podocytes (Tg(NPHS2-Ccr2)) on a nephropathy prone (DBA/2J) and CCR2 deficient (Ccr2−/−) background with heterozygous Ccr2+/− littermate controls. Diabetes was induced by streptozotocin. As expected, absence of CCR2 conferred kidney protection after nine weeks of diabetes. In contrast, transgenic CCR2 over expression in the podocytes of Ccr2−/− mice resulted in significantly increased albuminuria, blood urea nitrogen, histopathologic changes, kidney fibronectin and type-1 collagen expression, podocyte loss, and glomerular apoptosis after nine weeks of streptozotocin-induced diabetes. Interestingly, there was no concurrent increase in kidney macrophage recruitment or inflammatory cytokine levels in the mice. These findings support a direct role for CCR2 expression in podocytes to mediate diabetic renal injury, independent of monocyte/macrophage recruitment. Thus, targeting the CCR2 signaling cascade in podocytes could be a novel therapeutic approach for treatment of diabetic nephropathy.