Molecular biological analysis of GBM injury in glomerulonephritis

Alport综合征（Alport syndrome，AS）是一种以肾小球基底膜（glomerular basement membrane，GBM）复制或分裂为特征的先天性肾小球肾炎，其致病基因为IV型胶原α链（alpha（IV））。然而，基因异常和各种表型之间的关系仍然未知。最近，有报道称，由α 5（IV）（COL 4A 5）至α 6（IV）链基因（COL 4A 6）缺失引起的AS患者并发食管平滑肌肿瘤。我们一直在分析一个男性AS患者合并精神发育迟滞，但没有食管平滑肌肿瘤的基因突变。我们发现他有一个完全缺失的COL 4A 5，这可能涉及COL 4A 5和COL 4A 6之间的连接。在过去的一年中，我们进一步研究了对COL 4A 6的缺失程度，使用聚合酶链反应，发现COL 4A 6是一个 ...更多信息 也被完全删除了。因此推测，食管平滑肌肿瘤不是由COL 4A 5和COL 4A 6的完全缺失引起的，而是由多功能IV型胶原蛋白的表达引起的。大鼠实验模型中的肾小球肾炎和GBM损伤在抗Thy 1（ATS）肾炎中，通过单次注射ATS，系膜溶解随后发生系膜细胞增殖，而两次注射ATS则可引起进行性肾小球硬化和GBM损伤。虽然已知多种细胞因子和生长因子参与这些病理过程，但对这些因子在肾小球中的表达调节机制知之甚少。为了深入了解其机制，我们检测了转录因子AP-1和NF-κ B在ATS肾炎模型肾小球中的活化。结果发现，在系膜细胞增殖阶段，有1种转录因子被激活.我们还获得了肾小球表达诱导型一氧化氮合酶的证据，这可能在系膜和GBM损伤中发挥作用。少

The genomic mutation in type IV collagen in patients with glomerular basement membrane (GBM) injuryAlport syndrome (AS) is congenital glomerulonephritis characterized by the duplication or splitting of GBM and the responsible gene for AS has been identified as alpha chain of type IV collagen (alpha(IV)). However, the relationship between the gene abnormalities and various phenotypes remains unknown. Recently, it has been reported that patients with AS caused by deletions spanning the alpha5 (IV) (COL4A5) to alpha6( IV) chaingenes (COL4A6) are complicated by esophageal smooth muscle tumor. We havebeen analyzing a gene mutation in a male AS patient complicated with mental retardation but not with esophageal smooth muscle tumor. We had found that he had a complete deletion of the COL4A5 which may involve the junction between COL4A5 and COL4A6. In the last year, we have further investigated the extent of the deletion toward COL4A6 using polymerase chain reaction and found that COL4A6 was a … More lso completely deleted. It is thus speculated that, the esophageal smooth muscle tumoris not caused by a complete deletion of both COL4A5 and COL4A6 but may result from expression of mulfunctonal type IV collagen proteins.Glomerulonephritis and GBM injury in rat experimental modelIn anti-Thy 1 (ATS) nephritis, mesangiolysis followed by mesangial cell proliferation occurs transiently by single injection of ATS,while the twice injections of ATS induce progressiveglomerulosclerosis and GBM injury. Although various cytokines and growth factors are known to participate in these pathological processes, little is known about the mechanisms which regulate expression of these factors in glomeruli. To gain insight into the mechanisms, we examined the activation of transcription factor AP-1 and NF-kB in glomeruli in ATS nephritis model. We foundthat of the transcription factors were activated at the stage of mesangial cell proliferation. We also obtained the evidence of glomerular expression of inducible nitric oxide synthase which may play a role in mesangial and GBM injuries. Less