Study on a possible function of tenascin-C in wound healing of glomerulonephritis

没有Tenascin-C基因的小鼠没有表现出任何表型。Tenascin-C是一种多功能细胞外基质蛋白，在包括伤口愈合在内的许多重要生物学事件中都有表达。然而，现在很明显的是，一个基因缺失的表型往往取决于遗传背景。因此，我们通过将原始的Tenascin-C基因敲除小鼠回交到三个同源系：C57BL/6N、BALB/CA和GRS/A(GR)，产生了新的Tenascin-C基因敲除小鼠(KO)。并对可逆性肾损伤、哈布蛇毒诱导的增生性肾小球肾炎的病程进行了研究。在所有品系中，KO的病情较严重，但严重程度因品系而异。KO-GR表现出异常的再生反应，包括系膜细胞增殖减少，某些细胞因子和基质产生减少，导致肉芽组织形成不良。在培养中，来自KO-GR的系膜细胞具有与对照组相同的增殖能力和对细胞因子的反应，但有趣的是，为了实现这一潜力，它们需要与Tenascin-C接触。这些反应被抗Tenascin单抗阻断。目前的研究结果是迄今为止发现的第一个显示最戏剧性表型的报告，强烈表明Tenascin-C在解决肾脏炎症和KO发生的遗传背景方面的重要性。

Mice without the gene for tenascin-C, a multifunctional extracellular matrix protein expressed in many important biological events, including wound healing, did not show any phenotype. However, it is now obvious that the phenotype of deletion of one gene frequently depends on the genetic background. Therefore, we have newly generated tenascin-C knockout mice(KO)by backcrossing original KO into three congenic lines : C57BL/6N, BALB/cA, and GRS/A (GR). And we investigated the disease course of reversible kidney injury, Habu-snake venom-induced proliferative glomerulonephritis. In all strains, the disease was more severe in KO, but the severity varied with the strain. The KO-GR showed abnormal regenerative reactions, including reduced proliferation of mesangial cells, key players in glomerulonephritis, and reduced production of some kinds of cytokines and matrices, leading to poor formation of granulation tissue. In culture, the mesangial cells from the KO-GR had the same potential for proliferation and response to cytokines as controls, but interestingly, to achieve this potential, they required contact with tenascin-C.These reactions were blocked by an anti-tenascin monoclonal antibody. The results of the present study, the first report showing the most dramatic phenotype so far discovered, have strongly suggested the importance of tenascin-C in the resolution of the renal inflammation and that of the genetic background on which the KO was developed.