Role of MCP-1/CCR2 in renal fibrosis

对趋化因子及其同源受体的研究揭示了包括肾脏在内的各种炎症性疾病中白细胞迁移和激活的详细分子机制。肾脏常驻细胞上表达的趋化因子受体可能参与细胞增殖、蛋白尿和纤维化的形成。趋化因子的新的生物学功能将使其在肾脏疾病中的生物学功能超越趋化和炎症细胞的激活。重要的是，目前认为MCP-1及其同源受体CCR2参与了进行性肾脏纤维化的发生，这是进展性肾脏疾病的一个标志，尽管其病因包括糖尿病肾病。通过给予抗MCP-1中和抗体、CCR2拮抗剂和MCP-1突变体的选择性干预，MCP-1-CCR2通过减少I型胶原的沉积和减少转化生长因子-β的表达来改善进展性肾脏纤维化。CCR2基因靶向小鼠证实了这一MCP-1-CCR2依赖的进行性肾纤维化环路，提示阻断MCP-1-CCR2的治疗策略可能对进展性肾纤维化有利。

Studies of chemokines and their cognate receptors have shed light on the detailed molecular mechanisms of leukocyte trafficking and activation in various inflammatory diseases including renal ones.Chemokine receptors expressed on renal resident cells might be involved in proliferation, proteinuria and fibrogenesis.Novel biological functions of chemokines would expand their universe beyond chemotaxis and activation of inflammatory cells in renal diseases. Importantly, MCP-1 and its cognate receptor CCR2 are now considered to contribute to progressive renal fibrosis, which is a hallmark of progressive renal diseases despite their etiologies, including diabetic nephropathy.The selective intervention of MCP-1-CCR2 via the administration of anti-MCP-1 neutralizing antibodies, CCR2 antagonists and the MCP-1 mutant ameliorated progressive renal fibrosis by resulting in decrease in the deposit of type I collagen and in reduced expression of TGF-p. This MCP-1-CCR2-dependent loop for progressive renal fibrosis was confirmed in CCR2 gene targeted mice.These findings suggest that the therapeutic strategy of blocking MCP-1-CCR2 may prove beneficial for progressive renal fibrosis.