Division of Nephrology, Department of Internal Medicine, Saitama, Japan.
Lab Invest. 2010 Jun;90(6):867-80. doi: 10.1038/labinvest.2010.50. Epub 2010 Mar 1.
Interaction between epithelial cells and mesenchymal cells is essential in normal organ morphogenesis and in tissue repair after injury. Epimorphin, a mesenchymal protein that regulates epithelial morphogenesis through epithelial-mesenchymal interactions, has recently attracted attention as an important modulator of tissue repair. In this study we analyzed the role of epimorphin in renal fibrosis. We first found a progressive increase in epimorphin expression corresponding to the progression of renal fibrosis in mice with unilateral ureteral obstruction (UUO). To determine whether this expression has a role in the repair or progression of renal fibrosis, we analyzed a model of renal fibrosis repair, the UUO-release (UUO-R) model. Epimorphin expression was increased at 3 and 7 days after the UUO-R rather than on the day of release, but was decreased at 21 days after the release. Inhibition of endogenous epimorphin with anti-epimorphin antibody (MC-1) significantly delayed the repair of fibrosis. When compared with normal-IgG-injected mice, MC-1-injected mice showed significantly decreased renal matrix metalloproteinase (MMP)-2 and MMP-9 expressions by western blotting and increased expression of TGF-beta and collagen-I mRNA by real-time RT-PCR. Recombinant epimorphin induced prominent increases in MMP-2 and MMP-9 activities in the culture media of renal interstitial fibroblasts in vitro. These findings indicate that epimorphin has a pivotal role in the repair of renal fibrosis by modulating both extracellular matrix (ECM) degradation and its production.
上皮细胞和间充质细胞之间的相互作用对于正常器官形态发生和损伤后组织修复至关重要。表皮蛋白是一种通过上皮-间充质相互作用调节上皮形态发生的间充质蛋白，最近作为组织修复的重要调节剂引起了人们的关注。在这项研究中，我们分析了表皮蛋白在肾纤维化中的作用。我们首先发现，在单侧输尿管梗阻（UUO）小鼠中，随着肾纤维化的进展，表皮蛋白的表达逐渐增加。为了确定这种表达在肾纤维化的修复或进展中是否有作用，我们分析了肾纤维化修复模型，即 UUO 释放（UUO-R）模型。表皮蛋白的表达在 UUO-R 后 3 天和 7 天增加，而不是在释放当天增加，但在释放后 21 天减少。用抗表皮蛋白抗体（MC-1）抑制内源性表皮蛋白显著延迟了纤维化的修复。与注射正常 IgG 的小鼠相比，MC-1 注射小鼠的 Western blot 显示肾脏基质金属蛋白酶（MMP）-2 和 MMP-9 的表达明显减少，实时 RT-PCR 显示 TGF-β和胶原-I mRNA 的表达增加。重组表皮蛋白在体外诱导肾间质成纤维细胞培养物中 MMP-2 和 MMP-9 活性显著增加。这些发现表明，表皮蛋白通过调节细胞外基质（ECM）降解及其产生，在肾纤维化的修复中起关键作用。
