Megyesi J, Safirstein R L, Price P M
Department of Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.
J Clin Invest. 1998 Feb 15;101(4):777-82. doi: 10.1172/JCI1497.
The p21 protein is found in the nucleus of most cells at low levels and is induced to elevated levels after DNA damage, causing cell-cycle arrest. We have reported that p21 mRNA is rapidly induced to high levels in murine kidney after acute renal failure. The function(s) in the kidney of p21 induction in cisplatin-induced acute renal failure was studied with mice that are homozygous for a p21 gene deletion. After drug administration, as compared with their wild-type littermates, p21(-/-) mice display a more rapid onset of the physiologic signs of acute renal failure, develop more severe morphologic damage, and have a higher mortality. Therefore, the induction of p21 after cisplatin administration is a protective event for kidney cells. Using both bromodeoxyuridine incorporation and nuclear proliferating cell nuclear antigen detection, we found that cisplatin administration caused kidney cells to start entering the cell-cycle. However, cell-cycle progression is inhibited in wild-type mice, whereas kidney cells in the p21(-/-) mice progress into S-phase. We propose that p21 protects kidneys damaged by cisplatin by preventing DNA-damaged cells from entering the cell-cycle, which would otherwise result in death from either apoptosis or necrosis.
p21蛋白在大多数细胞的细胞核中含量较低，在DNA损伤后会被诱导升高，从而导致细胞周期停滞。我们曾报道，急性肾衰竭后小鼠肾脏中的p21 mRNA会迅速被诱导至高水平。利用p21基因缺失纯合的小鼠，研究了顺铂诱导的急性肾衰竭中p21诱导在肾脏中的作用。给药后，与野生型同窝小鼠相比，p21(-/-)小鼠急性肾衰竭的生理体征出现更快，形态学损伤更严重，死亡率更高。因此，顺铂给药后p21的诱导对肾细胞是一种保护作用。通过使用溴脱氧尿苷掺入法和核增殖细胞核抗原检测，我们发现顺铂给药会使肾细胞开始进入细胞周期。然而，野生型小鼠的细胞周期进程受到抑制，而p21(-/-)小鼠的肾细胞则进入S期。我们认为，p21通过阻止DNA损伤细胞进入细胞周期来保护顺铂损伤的肾脏，否则这些细胞会因凋亡或坏死而死亡。
