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Analyses for mechanisms of progression of kidney diseases by proteinuria

蛋白尿导致肾脏疾病进展的机制分析

基本信息

批准号：
18590914
负责人：
TAKENAKA Masaru
金额：
$ 2.43万
依托单位：
Kobe Women's University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590914/
关键词：
proteinuria oxidative stress Glia maturation factor 急性腎不全腎障害アポトーシス

项目摘要

We have reported that proteinuria induced the expression of brain specific protein, glia maturation factor-β (GMF) in the kidney (latiney Int 2002). It caused vulnerability to oxidative injury, resulting in apoptosis in cultured renal proximal tubular cells (T. Biol. Chem., 2003). To analyze the pathophysiological roles of GMF expression, we constructed transgenic mice expressing GMF (GMF-TG) and induced ischemia-reperfusion (IR) injury.The real-time PCR revealed that the expression of GMF in the kidney of GMF-TG was increased approximately eight times higher than that in wild type mice (C57BL/6) kidney. We performed Tunel assay to evaluate apoptotic cells in the kidney. It demonstrated that Tunel positive cells were significantly increased in the kidney of GMF-TG, indicating that GMF expression induced apoptosis in vivo, too. Thus, we hypothesized that I/R injury might cause severer damages in GMF-TG mice kidney than in wild type mice kidney. After right nephrectomy, ischemic injury w … More as induced by clamping of left renal artery and vein for 16 min. Surprisingly, serum creatinine levels were significantly low in GMF-TG compared to in normal mice (GMF-TG:0.611±0.07 mg/d1 versus normal:0.841±0.19 mg/d1, p<0.05, n=5 and 6, respectively) at 24hrs after reperfusion. Real-time PCR demonstrated that the expression of several mRNA such as p21, PAI-1 and CTGF in the normal and GMF-TG kidney before induction of I/R injury showed no significant differences. P21, PAI-1 and CTGF expression was up-regulated 24hr after I/R injury in wild type mice kidney (p21:60.3±12.4, PAI-1:90.6±18.2, CTGF:4.9±1.6 fold increases; n=4). It, however, was significantly decreased in GMF-TG kidney (p21:23.3±4.1, PAI-1:39.2±8.4, CTGF:2.4±0.3 fold increases; n=4) compared to those in normal mice at 24hr after 1/R. Data are provided as fold increase of each gene expression in wild type and GMF-TG mice kidney without I/R injury.Conclusion: The data indicated that GMF expression in vivo might have protective roles on I/R injury, although its expression resulted in apoptosis because of vulnerability to oxidative injury in vitro. Less

我们曾报道蛋白尿可诱导肾中脑特异性蛋白，神经胶质成熟因子-β (GMF)的表达（latiney, 2002）。它使培养的肾近端小管细胞易受氧化损伤，导致细胞凋亡。化学。, 2003)。为了分析GMF表达的病理生理作用，我们构建了表达GMF的转基因小鼠（GMF- tg）并诱导缺血再灌注（IR）损伤。实时荧光定量PCR结果显示，与野生型小鼠（C57BL/6）相比，GMF- tg肾脏中GMF的表达增加了约8倍。采用Tunel法观察肾脏细胞凋亡情况。结果表明，GMF- tg在肾脏中Tunel阳性细胞显著增加，表明GMF的表达在体内也诱导了细胞凋亡。因此，我们假设I/R损伤对转基因甘油三酯小鼠肾脏的损害可能比野生型小鼠更严重。右肾切除术后，左肾动静脉夹持16 min引起的缺血性损伤较多。令人惊讶的是，再灌注后24小时，GMF-TG组血清肌酐水平明显低于正常小鼠（GMF-TG:0.611±0.07 mg/d1，正常小鼠：0.841±0.19 mg/d1, p<0.05， n分别=5和6）。Real-time PCR结果显示，I/R损伤诱导前，正常肾和GMF-TG肾中p21、PAI-1、CTGF等几种mRNA的表达无显著差异。野生型小鼠肾I/R损伤后24hr P21、PAI-1、CTGF表达上调（p21:60 3±12.4,pai:90.6±18.2,CTGF:4.9±1.6倍，n=4）。1/R后24小时，与正常小鼠相比，GMF-TG肾组明显降低（p21:23.3±4.1,pai 1:39.2±8.4,CTGF:2.4±0.3倍，n=4）。数据为野生型和转基因甘油三酯小鼠无I/R损伤肾脏各基因表达量增加两倍。结论：GMF在体内的表达可能对I/R损伤有保护作用，但其在体外易受氧化损伤而导致细胞凋亡。少