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Effect of p53 on the variation of renal tubular epithelial cells after kidney ischemia/reperfusion injury

LI Kai-long~ 1, 2 , DU Xiao-lan~1, SONG Rui-hua~1, ZHAO Ling~1, HE Ya-ni~2, ZHANG Jian-guo~2, CHEN Lin~ 1* ~1Center of Medical Molecular Genetics,State Key Laboratory of Trauma, Burn and Combined Injury; ~2Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing 400042, China  
AIM: To observe the variation of renal tubular epithelial cells in p53(+/+) and p53(-/-)mice with young or old age at different time after kidney ischemia/reperfusion injury (IRI), and to investigate the contribution of p53 gene in the variation. METHODS: p53(+/+) and p53(-/-) male mice at age of 2 and 12 months were made ischemic by clamping left renal hila for 45 min. At 0, 1, 3 and 7 d, 1, 3 and 6 month after reflow, renal tissues were processed for morphometric observation and proliferating cell nuclear antigen(PCNA), apoptosis and senescence-associated β-galactosidase (SA-β-gal) analysis, using hematoxylin and eosin stain, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick-end labeling (TUNEL) and histochemical staining, respectively . RESULTS: Renal tubule necrosis was more severely in p53(-/-) mice and aged mice compared to p53(+/+) mice and young mice (P0.05), respectively. Apoptotic cells in p53(+/+) mice increased obviously compared to p53(-/-) mice (P0.05) at 7 d after IRI. In young wild-type mice, occasionally faint staining for SA-β-gal activity began to appear at 1 month, and obviously significantly increased at 3 and 6 months after IRI (P0.05), but in contralateral kidney at any time as mentioned above, and in the IRI kidneys in p53(-/-) mice at 1 and 3 months, there was almost no positive staining for SA-β-gal; occasionally positive staining for SA-β-gal was observed in the IRI kidney in p53(-/-) mice at 6 months after IRI. In p53 (-/-) and p53(+/+) aged mice, both kindeys had positive staining for SA-β-gal activity at 0d after IRI, but the level of the activity in p53(-/-) mice was much more lower than that in p53(+/+) mice (P0.05), then the level of the activity decreased notably at 1d in the IRI kidney (P0.05). Positive stain of nuclear PCNA in p53(+/+) young mice had no statistical significance compared to p53(+/+) aged mice (P0.05). But in p53(-/-) mice, significant positive staining for PCNA was tested, especially in young mice and in IRI kidneys (P0.05) . Correlation analysis between senescent and apoptotic cells in aged mice was made at 1d after IRI, then striking negative correlation was found between both of them in p53(+/+) mice (r=-0.82, P 0.05 ), but no statistical correlation in p53(-/-) mice(r=0.26, P0.05). CONCLUSION: IRI can accelerate renal tubular cell senescence and cellular death(both necrosis and apoptosis)after that. p53 gene may play an important role in the variation of tubular epithelial cells after kidney IRI.
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