Role of p53 in Chronic Kidney Disease

在p53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）。在测试p53的药理学抑制作用的实验中，在注射抗小鼠GBM血清的情况下向WT小鼠施用匹非林-α。与肾炎WT小鼠相比，肾炎KO小鼠的血清肌酐水平（Scr）显著升高。在肾病KO小鼠的肾脏中，肾小球和间质细胞随着细胞外基质的扩张而增殖。肾炎KO小鼠的增殖变化伴随着细胞周期蛋白依赖性激酶2（CDK 2）的激活。类似地，在肾炎WT小鼠中p53的药理学抑制导致细胞增殖和CDK 2活化增加，这被选择性CDK 2抑制剂roscovitine完全逆转。这些结果表明，内源性p53抑制过度增殖反应，并调节细胞外基质的稳态抗GBM GN。

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.