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

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 E-2 (iPGE(2)) 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 iPGE(2). Because expression of retinoic acid receptor-beta (RAR-beta) is dependent on iPGE(2) and because RAR-beta is a regulator of cell survival and proliferation, we hypothesized that RAR-beta 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-5 antagonist LE-135; ii) DIDS increased the expression of RAR-beta 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-beta expression decreased in cisplatin-treated PTC, RAR-beta over-expression prevented cisplatin's toxicity. RAR-beta agonist CH55 or RAR pan-agonist alltrans retinoic acid did not prevent cisplatin's toxicity, which suggests that RAR-beta does not protect PTC through activation of gene transcription. In conclusion, RAR-beta 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.