progressive mesangial cell proliferation and expansion in mice overepxressed mesangium-predominant serine protease inhibitor, megsin,

我们采用小鼠分子遗传学方法，在小鼠体内过量表达人megsin基因。一些megsin转基因小鼠在40周龄时表现出肾小球形态学变化。病理改变包括系膜区细胞增多和系膜基质扩张。此外，当我们在野生型和megsin转基因小鼠中诱导抗肾小球基底膜（GBM）肾炎时，系膜扩张仅在转基因小鼠中持续存在。megsin转基因小鼠的肾小球病变伴随着增强的免疫复合物沉积以及免疫球蛋白和补体。免疫复合物（IC）沉积在这些小鼠中的主要机制不太可能是增加产量，因为转基因小鼠中循环IC的水平充其量是微不足道的。这种现象的解释应该是肾小球系膜细胞清除免疫复合物等大分子的能力下降。我们推测，megsin基因的过度表达可能导致系膜功能障碍，损害IC的降解和处置，并改变系膜基质的微环境。我们进行了半肾切除术，以加速megsin转基因小鼠的肾小球损伤。半肾切除转基因小鼠出现局灶节段性系膜扩张，并伴有蛋白尿。该转基因小鼠的半肾切除模型可作为研究肾小球疾病发病机制的工具。

We employed mouse molecular genetic approaches and overexpressed human megsin gene in mice. Some megsin transgenic mice exhibited glomerular morphological changes at 40 weeks of age. The pathological changes included increased number of cells in the mesangial area and an expansion of mesangial matrix. Furthermore, when we induced anti-glomerular basement membrane (GBM) nephritis in wild type and megsin transgenic mice, mesangial expansion persisted only in the transgenic mice. The glomerular lesions in megsin transgenic mice were accompanied by an augmented immune complex deposition together with immunoglobulins and complement. It is unlikely that a primary mechanism of immune complex (IC) deposition in these mice was augmented production, because the levels of circulating IC in transgenic mice were at best trivial. The explanation of this phenomenon should be found in a decreased capacity of mesangial cells to clear macromolecules such as immune complexes. We speculate that overexpression of megsin, a mesangium predominant gene, might lead to mesangial dysfunction, impair the degradation and disposal of IC, and alter the microenvironment of mesangial matrix. We performed hemi-nephrectomy to accelerate glomerular injury in megsin transgenic mice. Hemi-nephrectomized transgenic mice developed focal segmental mesangial expansion, which was associated with proteinuria. Hemi-nephrectomized model of this transgenic mice might serve as a tool to investigate mechanisms of glomerular disease.