Role of p53 in Chronic Kidney Disease

p53 在慢性肾脏病中的作用

• 批准号: 23591182
• 负责人: HAMANO Yuki
• 金额: $ 3.24万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591182/
• 关键词: p53; Anti-GBM Disease; CDK2; 18型コラーゲン; エンドスタチン; 糖尿病性腎症; 血管新生; 老化

Anti-glomerular basement membrane (GBM) glomerulonephritis (GN) was induced in p53-null (KO) and wild-type (WT) mice. In the experiment to test the effect of pharmacological inhibition of p53, WT mice were administered pifithrin-alpha with the injection of anti-mouse GBM serum. Serum creatinine levels (Scr) were significantly elevated in nephritic KO mice compared with nephritic WT mice. In the kidney of nephritic KO mice, glomerular and interstitial cells were proliferated with extracellular matrix expansion. The proliferative change in the nephritic KO mice was accompanied by the activation of cyclin-dependent kinase 2 (CDK2). Similarly, the pharmacological inhibition of p53 in nephritic WT mice led to the increased cell proliferation and CDK2 activation, which were completely reversed by roscovitine, a selective CDK2 inhibitor. These findings indicate that endogenous p53 inhibits the excessive proliferative responses and regulates extracellular matrix homeostasis during anti-GBM GN.

在p53基因缺失(KO)和野生型(WT)小鼠中诱导抗肾小球基底膜(GBM)肾小球肾炎(GN)。为验证P53的药理抑制作用，WT小鼠在注射抗小鼠GBM血清的同时给予匹非菊酯-α。肾炎性KO小鼠与肾炎性WT小鼠相比，血清肌酐水平(Scr)显著升高。在肾炎性KO小鼠肾脏，肾小球和间质细胞随着细胞外基质的扩张而增殖。肾炎性KO小鼠的增殖性改变伴随着细胞周期蛋白依赖性激酶2(CDK2)的激活。同样，肾炎性WT小鼠P53的药理抑制导致细胞增殖和CDK2激活增加，这一作用可被选择性CDK2抑制剂Roscovitine完全逆转。这些结果表明，在抗GBM GN过程中，内源性P53抑制了过度的增殖反应，调节了细胞外基质的稳态。

项目成果

Physiological Levels of Endostatin Suppress Glomerular Vascular Leak and Inflammation in Diabetic Nephropathy

内皮抑素的生理水平抑制糖尿病肾病肾小球血管渗漏和炎症

• 发表时间: 2011
• 作者: 宇田川由紀;小川真;佐藤信範;上田善彦;横須賀收;浜野有記
• 通讯作者: 浜野有記

Physiological Levels of Endostatin Suppress Renal Injury

内皮抑素的生理水平抑制肾损伤

• 作者: 浜野有記;宇田川由紀;上田善彦;横須賀收;小川真
• 通讯作者: 小川真

Collagen XVIII and Endostatin Have Differential Roles in Early Stages of Diabetic Nephropathy

XVIII 胶原蛋白和内皮抑素在糖尿病肾病的早期阶段具有不同的作用

• 作者: 浜野有記;宇田川由紀;浜野理恵;上田善彦;小川真
• 通讯作者: 小川真

p53 Deficiency Exacerbates Immune-Medical Glomerulonephritis

p53 缺乏会加剧免疫医学性肾小球肾炎

• 发表时间: 2011
• 作者: 浜野有記;木村亮太;宇田川由紀;上田善彦;横須賀收;小川真
• 通讯作者: 小川真

p53 Deficiency Exacerbates Immune-Mediated Glomerulonephritis

p53 缺乏会加剧免疫介导的肾小球肾炎

• 发表时间: 2011
• 作者: 浜野有記;木村亮太;宇田川由紀;上田善彦;横須賀收;小川真
• 通讯作者: 小川真