Retinoic acid receptor-beta prevents cisplatin-induced proximal tubular cell death

Abstract

Cisplatin's toxicity in renal tubular epithelial cells limits the therapeutic efficacy of this antineoplastic drug. In cultured human proximal tubular HK-2 cells (PTC) a prostaglandin uptake transporter (PGT)-dependent increase in intracellular prostaglandin E2 (iPGE2) mediates cisplatin's toxicity (i.e. increased cell death and loss of cell proliferation) so that it is prevented by PGT inhibitors. Here we found in cisplatin-treated PTC that 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), a PGT inhibitor, prevented cisplatin's toxicity but not the increase in iPGE2. Because expression of retinoic acid receptor-β (RAR-β) is dependent on iPGE2 and because RAR-β is a regulator of cell survival and proliferation, we hypothesized that RAR-β might mediate the protective effect of DIDS against cisplatin's toxicity in PTC. Our results confirmed this hypothesis because: i) protection of PTC by DIDS was abolished by RAR-β antagonist LE-135; ii) DIDS increased the expression of RAR-β in PTC and prevented its decrease in cisplatin-treated PTC but not in cisplatin-treated human cervical adenocarcinoma HeLa cells in which DIDS failed to prevent cisplatin's toxicity; iii) while RAR-β expression decreased in cisplatin-treated PTC, RAR-β over-expression prevented cisplatin's toxicity. RAR-β agonist CH55 or RAR pan-agonist all-trans retinoic acid did not prevent cisplatin's toxicity, which suggests that RAR-β does not protect PTC through activation of gene transcription. In conclusion, RAR-β might be a new player in cisplatin-induced proximal tubular injury and the preservation of its expression in proximal tubules through treatment with DIDS might represent a novel strategy in the prevention of cisplatin's nephrotoxicity without compromising cisplatin's chemotherapeutic effect on cancer cells.