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

急性基本自限性肾小球损伤发展为慢性进行性肾小球硬化的分子机制尚不清楚。我们试图确定在慢性和进行性肾小球硬化的肾脏中主要表达的基因，而在急性和短暂性肾小球肾炎中较少表达。单侧肾切除术后应用单克隆抗thy - 1诱导大鼠进行性肾小球硬化。1抗体（OX-7）注射液（Nx）。我们通过将Nx的dna与假手术大鼠的dna进行减法杂交，确定了在慢性肾小球硬化中主要表达的基因。这些基因可能在促进初始肾小球损伤导致慢性和进行性肾小球硬化的过程中起重要作用。我们报道了血管紧张素II型1受体拮抗剂（AT1Ra）治疗可以减少Nx大鼠的蛋白尿和形态学改变。此外，AT1Ra抑制核蛋白与tgf - β控制元件（TCE）的结合活性，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。我们的结论是AT1Ra降低了TCE的活性。它存在于α - smc基因的启动子病变中。我们还研究了大量肾活检标本的形态学，并报道了小管间质病变在糖尿病肾小球硬化的进展中作为肾小球病变是重要的。探讨糖尿病患者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剂-1、ACE和载脂蛋白E的基因多态性。我们已经报道pai - 1和ACE基因多态性与风险相关。大动脉并发症和apoE4杂交是肾病的保护因素。

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.