Protective effects of retinoic acid on cadmium toxicity in human proximal tubular epithelial cells

Abstract

Cadmium (Cd) is a toxic heavy metal that induces proximal tubular cell damage. Previously, we identified that retinoic acid receptor (RAR) activity was suppressed in the kidney of Cd-exposed mice. In addition, peroxisome proliferator-activated receptor δ, PPARδ, contributed to the modification of Cd toxicity in HK-2 human proximal tubular cells. In this study, we investigated the protective effects of retinoic acid (RA) and its precursor, retinol, against Cd-induced cytotoxicity in HK-2 cells. Pretreatment with RA or retinol significantly reduced Cd toxicity. Knockdown of RARA, RARG, or PPARD did not alter the protective effects of RA; moreover, the double knockdown of RARA and RARG partly suppressed the RA-reduced Cd toxicity. This suggested that RA may reduce Cd toxicity by a receptor-independent mechanism. Furthermore, RA did not affect the expression of metallothionein genes (MT-1X and MT-2A) or the intracellular accumulation of Cd after Cd treatment. RA pretreatment suppressed Cd-induced apoptosis, partly by inhibiting caspase-3 activation. These findings suggest that RA prevents Cd toxicity via a novel, receptor-independent mechanism involving the suppression of apoptosis.