Role of the Increase in p21 in Cisplatin-Induced Acute Renal Failure in Rats

Abstract. The goal of this study was to clarify the role of p21, a cyclin-dependent kinase inhibitor, in acute renal failure (ARF). This was accomplished with the examination of the renal expression of p21 in cisplatin (CDDP)-induced ARF and in rechallenge injury with CDDP. The injection of CDDP (5 mg/kg) into rats induced increases in serum creatinine and tubular damage and the number of in situ DNA nick end labeling—positive cells, which peaked at day 5, followed by recovery to control levels by day 14. The rechallenge with the same dose of CDDP 14 d after the first dose of CDDP induced significantly less injury and no significant increase in in situ DNA nick end labeling—positive cells. The first CDDP dose significantly increased p53-positive nuclei at day 1, which disappeared by day 5, and the number of p21-positive nuclei, which had two peaks on days 3 and 9. The number of proliferating cell nuclear antigen (PCNA)-positive nuclei peaked at days 3 and 12. A significant increase in the incorporation of 5-bromo 2′-deoxyuridine (BrdU) was found at day 5 and peaked at day 7. The second injection of CDDP induced significant increases in the number of p21-, p53-, and PCNA-positive nuclei within 2 d but did not affect the incorporation of BrdU. These findings suggested that ( 1 ) CDDP induced two peaks of the increase in p21; ( 2 ) the first peak occurred shortly after CDDP and was accompanied by overexpression of p53 and PCNA but not with BrdU incorporation, possibly reflecting G1 arrest and DNA repair; ( 3 ) the second peak of p21 occurred through an p53-independent pathway and may contribute to cell differentiation; and ( 4 ) the overexpression of p21 and PCNA in rechallenge injury may contribute to acquired resistance in CDDP-induced ARF via enhanced DNA repair.