Lack of the growth factor midkine enhances survival against cisplatin-induced renal damage
Lack of the growth factor midkine enhances survival against cisplatin-induced renal damage
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DOI：
10.1016/s0002-9440(10)63417-7
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发表时间：
2004-11-01
影响因子：
6
通讯作者：
Muramatsu, T
中科院分区：
文献类型：
--
作者：
Kawai, H;Sato, W;Muramatsu, T
虽然顺铂直接作用于近端小管上皮细胞并导致细胞死亡，但关于其继发性效应（如炎症）的生物学意义知之甚少。生长因子中期因子在近端小管中高度表达，并对顺铂肾毒性发挥矛盾活性，即抗凋亡和趋化活性。在这里，我们报告说，中期因子缺陷小鼠显示出显着高于野生型小鼠的存活率。尽管中期因子具有抗凋亡活性，但野生型小鼠的血尿素氮和肾小管变性及凋亡水平较高。我们发现中性粒细胞的募集在野生型小鼠中更增强，这与中期因子的趋化活性一致。在野生型小鼠中中期因子的表达持续24小时，然后急剧下降。中期因子反义寡脱氧核苷酸对野生型小鼠的预给药抑制中期因子表达，从而抑制中性粒细胞浸润。值得注意是，中性粒细胞浸润、细胞凋亡和血尿素氮的升高依次变得明显，即分别在顺铂给药后1、2和3天。这些发现表明，涉及中期因子的早期分子事件诱导炎症反应，其回路最终促进近端小管上皮细胞的死亡。这些结果表明炎症在顺铂诱导的肾损害中起着至关重要的作用，并为其预防提供了候选的分子靶点。
Although cisplatin acts directly on proximal tubule epithelial cells and causes cell death, little is known regarding the biological significance of its secondary effects, such as inflammation. The growth factor midkine is highly expressed in the proximal tubule and exerts ambivalent activities as to cisplatin nephrotoxicity, ie, anti-apoptotic and chemotactic ones. Here we report that midkine-deficient mice show a significantly higher survival rate than wild-type mice. The levels of blood urea nitrogen and tubular degeneration and apoptosis were higher in wild-type mice despite the anti-apoptotic activity of midkine. We found that recruitment of neutrophils was more enhanced in wild-type mice, this being consistent with the chemotactic activity of midkine. Midkine expression in wild-type mice persisted for 24 hours, and then dramatically decreased. Preadministration of midkine anti-sense oligodeoxyribonucleotide to wildtype mice suppressed midkine expression, and consequently neutrophil infiltration. it is of note that neutrophil infiltration, apoptosis, and elevation of blood urea nitrogen became conspicuous sequentially, namely 1, 2, and 3 days after cisplatin administration, respectively. These findings suggest that early molecular events involving midkine induce inflammatory response and their circuits eventually enhance the death of the proximal tubule epithelial cells. The results indicate the crucial role of inflammation in cisplatin-induced renal damage, and provide a candidate molecular target for its prevention.