title: 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.
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Miyaji
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kato
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fujigaki
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hishida
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002945:Cisplatin / Q000633:toxicity*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin