Sato W, Kadomatsu K, Yuzawa Y, Muramatsu H, Hotta N, Matsuo S, Muramatsu T
Department of Internal Medicine III and Biochemistry, Nagoya University School of Medicine, Nagoya, Japan.
J Immunol. 2001 Sep 15;167(6):3463-9. doi: 10.4049/jimmunol.167.6.3463.
Midkine (MK) is a multifunctional heparin-binding protein and promotes migration of neutrophils, macrophages, and neurons. In the normal mouse kidney, MK is expressed in the proximal tubules. After renal ischemic reperfusion injury, its expression in proximal tubules was increased. Immediate increase of MK expression was found when renal proximal tubular epithelial cells in culture were exposed to 5 mM H(2)O(2). Histologically defined tubulointerstitial damage was less severe in MK-deficient (Mdk(-/-)) than in wild-type (Mdk(+/+)) mice at 2 and 7 days after ischemic reperfusion injury. Within 2 days after ischemic injury, inflammatory leukocytes, of which neutrophils were the major population, were recruited to the tubulointerstitium. The numbers of infiltrating neutrophils and also macrophages were lower in Mdk(-/-) than in Mdk(+/+) mice. Induction of macrophage inflammatory protein-2 and macrophage chemotactic protein-1, chemokines for neutrophils and macrophages, respectively, were also suppressed in Mdk(-/-) mice. Furthermore, renal tubular epithelial cells in culture expressed macrophage inflammatory protein-2 in response to exogenous MK administration. These results suggested that MK enhances migration of inflammatory cells upon ischemic injury of the kidney directly and also through induction of chemokines, and contributes to the augmentation of ischemic tissue damage.
中期因子（MK）是一种多功能肝素结合蛋白，可促进中性粒细胞、巨噬细胞和神经元的迁移。在正常小鼠肾脏中，MK在近端小管中表达。肾缺血再灌注损伤后，其在近端小管中的表达增加。当培养的肾近端小管上皮细胞暴露于5 mM H₂O₂时，发现MK表达立即增加。在缺血再灌注损伤后2天和7天，组织学定义的肾小管间质损伤在MK缺陷（Mdk⁻/⁻）小鼠中比野生型（Mdk⁺/⁺）小鼠中较轻。在缺血损伤后2天内，炎症白细胞（其中中性粒细胞是主要群体）被募集到肾小管间质。Mdk⁻/⁻小鼠中浸润的中性粒细胞和巨噬细胞数量均低于Mdk⁺/⁺小鼠。巨噬细胞炎症蛋白-2和巨噬细胞趋化蛋白-1（分别为中性粒细胞和巨噬细胞的趋化因子）的诱导在Mdk⁻/⁻小鼠中也受到抑制。此外，培养中的肾小管上皮细胞对外源MK给药有反应，表达巨噬细胞炎症蛋白-2。这些结果表明，MK在肾脏缺血损伤时直接并通过诱导趋化因子增强炎症细胞的迁移，并导致缺血组织损伤的加重。
