Inhibition of p21 modifies the response of cortical proximal tubules to cisplatin in rats.

The purpose of this study was to evaluate whether upregulated p21, a cell cycle-inhibitory protein, contributes to cisplatin (CDDP)-induced acute renal failure (ARF) and to acquired resistance to rechallenge injury with CDDP in rats. ARF was induced in rats by injection of CDDP (5 mg/kg) and rechallenge injury to CDDP by the same dose of CDDP 14 days after the first CDDP injection. Rats were treated with p21 antisense oligodeoxynucleotide (ODN) or its vehicle, p21 sense ODN, every 36 h from days 0 to 5 for single CDDP and from days 13 to 19 for rechallenge injury and killed at day 3, 5, 16, or 19. The uptake of FITC-labeled p21 antisense ODNs by cortical proximal tubule (PT) cells was much greater than by PT cells in the outer stripe of outer medulla (OSOM). Administration of antisense induced partial downregulation of p21 mRNA and protein levels in whole kidneys with single CDDP treatment and its rechallenge injury. Antisense significantly aggravated PT necrosis and decreased the number of p21-positive PT cells in the cortex but not in the OSOM in both CDDP-induced ARF and its rechallenge injury. However, antisense did not alter serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Our findings suggested that p21 plays, at least in part, a cytoprotective role in cortical PTs exposed to CDDP, although this does not contribute to renal dysfunction when judged by Scr and BUN levels. Because antisense may not adequately be taken up and/or function in PTs in the OSOM, the role of p21 in PTs in the OSOM in CDDP-induced ARF remains to be clarified.