Atypical, bidirectional regulation of cadmium-induced apoptosis via distinct signaling of unfolded protein response

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Abstract
Cadmium is a widely distributed nephrotoxic metal that causes renal tubular injury. In this report, we investigated involvement of endoplasmic reticulum (ER) stress and individual unfolded protein responses in cadmium-initiated apoptosis of tubular epithelial cells. Cadmium chloride (CdCl2) induced expression of endogenous ER stress markers, GRP78, GRP94 and CHOP in vitro and in vivo, and subsequently caused cytological changes typical of apoptosis. Attenuation of ER stress by transfection with ER chaperone GRP78 or ORP150 suppressed CdCl2-triggered apoptosis. In response to CdCl2, phosphorylation of RNA-dependent protein kinase-like ER kinase (PERK) and eukaryotic translation initiation factor 2α (eIF2α) was observed. Enhanced phosphorylation of eIF2α attenuated, whereas inhibition of eIF2α exacerbated CdCl2-induced apoptosis. Activating transcription factor 6 (ATF6) was also activated by CdCl2 and blockade of this process suppressed induction of CHOP and thereby improved cell survival. CdCl2 also triggered activation of the inositol-requiring ER-to-nucleus signal kinase 1 (IRE1)–X-box-binding protein 1 (XBP1) pathway and inhibition of XBP1 attenuated apoptosis independent of GRP78 and CHOP. c-Jun N-terminal kinase (JNK), another molecule downstream of IRE1, was also phosphorylated by CdCl2 and its inhibition attenuated apoptosis. These results evidenced bidirectional regulation of apoptosis in cadmium-exposed cells. The ATF6 and IRE1 pathways cooperatively caused apoptosis via induction of CHOP, activation of XBP1 and phosphorylation of JNK, and the PERK–eIF2α pathway counteracted the proapoptotic processes.