Identification and fuctional analysis of genes that promote progression of glomerulosclerosis and investingation of regulatory mechantsm of the gene expression.

急性和基本自限性肾小球损伤进展为慢性和进行性肾小球硬化的分子机制尚不清楚。我们试图找出主要在慢性和进行性肾小球硬化的肾脏中表达，而在急性和短暂性肾小球肾炎中表达较少的基因。在大鼠中通过单侧肾切除术随后单克隆抗Thy 1.1抗体（OX-7）注射（Nx）诱导进行性肾小球硬化。我们已经确定了基因表达主要是在慢性肾小球硬化症的消减杂交的cDNA从NX与过量的那些假手术大鼠。这些基因可能在促进肾小球早期损伤导致慢性和进行性肾小球硬化的过程中起重要作用。我们已经报道用血管紧张素Ⅱ 1型受体拮抗剂（AT 1 Ra）治疗可减少Nx大鼠的蛋白尿和形态学改变。此外，AT 1 Ra抑制核蛋白与TGF-β控制元件（TCE）的结合活性，并降低α-平滑肌肌动蛋白的表达。这是众所周知的肾纤维化的标志物。结论AT 1 Ra可降低α-平滑肌细胞基因启动子损伤中TCE的活性，并对大量肾活检标本进行形态学研究，发现肾小管间质病变与肾小球病变一样在糖尿病肾小球硬化的发生发展中起重要作用，探讨糖尿病肾病发生的遗传背景。我们分析了NIDDM患者纤溶酶原激活物抑制物-1、ACE和载脂蛋白E的基因多态性。我们已经报道PAI-1和ACE基因多态性与高血压的风险有关。主要动脉并发症，apoE 4 β是肾病的保护因子。

The molecular mechanisms, in which acute and basically self-limited glomerular injury advance to chronic and progressive glomerulosclerosis, is unknown. We tried to identify genes expressed predominantly in the kidney of chronic and progressive glomeruloscierosis but less in acute and transient glomerulonephritis. Progressive glomerulosclerosis was induced in rats by unilateral nephrectomy followed by monoclonal anti-Thy 1 .1 antibody (OX-7) injection (Nx). We have identified genes expressed predominantly in chronic glomerulosclerosis by subtraction hybridization of cDNAs from Nx with an excess amount of those from Sham operated rats. These genes may play important roles in the process which promotes initial glomerular injury to result in chronic and progressive glomerulosclerosis.We have reported that treatment with Angiotensin II type 1 receptor antagonist (AT1Ra) reduced proteinuria and morphological change in Nx rats. Also, AT1Ra inhibited binding activity of nuclear proteins to TGF-beta control element (TCE) and reduced alpha-smooth muscle actin expression. which is well known as a marker of kidney fibrosis. We concluded that AT1Ra reduced the activity of TCE.which exists in the promotor lesion of alpha-SMC gene.We also studied morphologically a large number of kidney biopsy specimens, and reported that tubulointerstitial lesion was important as glomerular lesion in the progression of diabetic glomerulosclerosis.To investigate the genetic background for occurrence of nephropathy in diabetic patients. we analyzed gene polymorphism of plasminogen activator inhibitor-1, ACE, and apolipoprotein E in NIDDM patients. We have reported that PAI-l and ACE gene polymorphism are associated with the risk of. major artery complications and that apoE4 allel is a protective factor for nephropathy.