Role of p53 in Chronic Kidney Disease

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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.