Pleiotrophin triggers inflammation and increased peritoneal permeability leading to peritoneal fibrosis.
Pleiotrophin triggers inflammation and increased peritoneal permeability leading to peritoneal fibrosis.
复制标题
DOI：
10.1038/ki.2011.305
复制
发表时间：
2012-01
影响因子：
19.6
通讯作者：
H. Yokoi;M. Kasahara;K. Mori;Y. Ogawa;T. Kuwabara;Hirotaka Imamaki;T. Kawanishi;Kenichi Koga;
中科院分区：
文献类型：
--
作者：
H. Yokoi;M. Kasahara;K. Mori;Y. Ogawa;T. Kuwabara;Hirotaka Imamaki;T. Kawanishi;Kenichi Koga;
长期腹膜透析诱导腹膜纤维化伴中皮下纤维化组织。虽然血管生成和炎症介质参与了腹膜纤维化，但确切的分子机制尚不清楚。为了研究这一点，我们使用微阵列分析，并比较了对照组和葡萄糖酸氯己定（CG）诱导的腹膜纤维化小鼠腹膜的基因表达谱。43个高度上调的基因之一是多效因子，一种中期因子家族成员，其表达也被用于腹膜透析治疗小鼠的溶液上调。这种生长因子存在于小鼠下层间皮致密区的成纤维细胞和间皮细胞中，以及人腹膜活检样本和腹膜透析液流出物中。重组多效生长因子刺激培养小鼠间皮细胞的有丝分裂和迁移。我们发现，在野生型小鼠中，CG处理增加了腹膜通透性（通过平衡测量），增加了TGF-β1、结缔组织生长因子和纤连蛋白、TNF-α和IL-1β的mRNA表达，并导致CD 3阳性T细胞浸润，并导致大量Ki-67阳性增殖细胞。所有这些参数降低CG处理的多效生长因子基因敲除小鼠的腹膜组织。因此，多效生长因子的上调似乎在腹膜损伤期间的纤维化和炎症中起作用。
Long-term peritoneal dialysis induces peritoneal fibrosis with submesothelial fibrotic tissue. Although angiogenesis and inflammatory mediators are involved in peritoneal fibrosis, precise molecular mechanisms are undefined. To study this, we used microarray analysis and compared gene expression profiles of the peritoneum in control and chlorhexidine gluconate (CG)-induced peritoneal fibrosis mice. One of the 43 highly upregulated genes was pleiotrophin, a midkine family member, the expression of which was also upregulated by the solution used to treat mice by peritoneal dialysis. This growth factor was found in fibroblasts and mesothelial cells within the underlying submesothelial compact zones of mice, and in human peritoneal biopsy samples and peritoneal dialysate effluent. Recombinant pleiotrophin stimulated mitogenesis and migration of mouse mesothelial cells in culture. We found that in wild-type mice, CG treatment increased peritoneal permeability (measured by equilibration), increased mRNA expression of TGF-β1, connective tissue growth factor and fibronectin, TNF-α and IL-1β expression, and resulted in infiltration of CD3-positive T cells, and caused a high number of Ki-67-positive proliferating cells. All of these parameters were decreased in peritoneal tissues of CG-treated pleiotrophin-knockout mice. Thus, an upregulation of pleiotrophin appears to play a role in fibrosis and inflammation during peritoneal injury.