Role of p53 in Chronic Kidney Disease

在p53-null （KO）和野生型（WT）小鼠中诱导抗肾小球基底膜（GBM）型肾小球肾炎（GN）。在实验中，为了检验p53的药理抑制作用，我们给WT小鼠注射了抗小鼠GBM血清，同时注射了氟虫腈- α。与WT小鼠相比，KO小鼠血清肌酐水平（Scr）显著升高。在肾炎KO小鼠肾脏中，肾小球和间质细胞增生，细胞外基质扩增。肾病KO小鼠的增殖变化伴随着细胞周期蛋白依赖性激酶2 （CDK2）的激活。同样，在肾病WT小鼠中，对p53的药物抑制导致细胞增殖和CDK2激活增加，而选择性CDK2抑制剂罗斯科维汀完全逆转了这一点。这些发现表明，在抗gbm GN过程中，内源性p53抑制过度增殖反应并调节细胞外基质稳态。

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.