Lee Eun Young, Chung Choon Hee, Khoury Charbel C, Yeo Tet Kin, Pyagay Petr E, Wang Amy, Chen Sheldon
Division of Nephrology/Hypertension, Northwestern University, Chicago, Illinois 60611, USA.
Am J Physiol Renal Physiol. 2009 Jul;297(1):F85-94. doi: 10.1152/ajprenal.90642.2008. Epub 2009 May 6.
The role of monocyte chemoattractant protein-1 (MCP-1) in diabetic nephropathy is typically viewed through the lens of inflammation, but MCP-1 might exert noninflammatory effects on the kidney cells directly. Glomerular podocytes in culture, verified to express the marker nephrin, were exposed to diabetic mediators such as high glucose or angiotensin II and assayed for MCP-1. Only transforming growth factor-beta (TGF-beta) significantly increased MCP-1 production, which was prevented by SB431542 and LY294002, indicating that signaling proceeded through the TGF-beta type I receptor kinase and the phosphatidylinositol 3-kinase pathway. The TGF-beta-induced MCP-1 was found to activate the podocyte's cysteine-cysteine chemokine receptor 2 (CCR2) and, as a result, enhance the cellular motility, cause rearrangement of the actin cytoskeleton, and increase podocyte permeability to albumin in a Transwell assay. The preceding effects of TGF-beta were replicated by treatment with recombinant MCP-1 and blocked by a neutralizing anti-MCP-1 antibody or a specific CCR2 inhibitor, RS102895. In conclusion, this is the first description that TGF-beta signaling through PI3K induces the podocyte expression of MCP-1 that can then operate via CCR2 to increase cellular migration and alter albumin permeability characteristics. The pleiotropic effects of MCP-1 on the resident kidney cells such as the podocyte may exacerbate the disease process of diabetic albuminuria.
单核细胞趋化蛋白-1（MCP-1）在糖尿病肾病中的作用通常是从炎症角度来审视的，但MCP-1可能直接对肾细胞发挥非炎症性作用。培养的肾小球足细胞经证实表达标志蛋白nephrin，将其暴露于高糖或血管紧张素II等糖尿病介质中，并检测MCP-1。只有转化生长因子-β（TGF-β）能显著增加MCP-1的产生，而SB431542和LY294002可抑制这种增加，这表明信号传导是通过TGF-β I型受体激酶和磷脂酰肌醇3-激酶途径进行的。发现TGF-β诱导产生的MCP-1可激活足细胞的半胱氨酸-半胱氨酸趋化因子受体2（CCR2），结果在Transwell实验中增强细胞运动性、导致肌动蛋白细胞骨架重排并增加足细胞对白蛋白的通透性。用重组MCP-1处理可重现TGF-β的上述作用，而用中和性抗MCP-1抗体或特异性CCR2抑制剂RS102895可阻断这些作用。总之，这是首次描述通过PI3K的TGF-β信号传导诱导足细胞表达MCP-1，然后MCP-1可通过CCR2发挥作用，增加细胞迁移并改变白蛋白通透性特征。MCP-1对足细胞等驻留肾细胞的多效性作用可能会加剧糖尿病蛋白尿的疾病进程。
