PloS one 2013,
Kato, Hironori; Katoh, Ryohei; Kitamura, Masanori
Cadmium (Cd) causes generation of reactive oxygen species (ROS) that trigger renal tubular injury. We found that rapamycin, an inhibitor of mTORC1, attenuated Cd-induced apoptosis in renal tubular cells. Knockdown of Raptor, a positive regulator of mTORC1, also had the similar effect. However, rapamycin did not alter generation of ROS, suggesting that mTORC1 is a target downstream of ROS. Indeed, ROS caused activation of mTORC1, which contributed to induction of a selective branch of the unfolded protein response (UPR); i.e., the IRE1 pathway. Although Cd triggered three major UPR pathways, activation of mTORC1 by Cd did not contribute to induction of the PERK-eIF2α and ATF6 pathways. Consistently, knockdown of Raptor caused suppression of JNK without affecting the PERK-eIF2α pathway in Cd-exposed cells. Knockdown of TSC2, a negative regulator of mTORC1, caused activation of mTORC1 and enhanced Cd induction of the IRE1-JNK pathway and apoptosis without affecting other UPR branches. Inhibition of IRE1α kinase led to suppression of JNK activity and apoptosis in Cd-treated cells. Dominant-negative inhibition of JNK also suppressed Cd-induced apoptosis. In contrast, inhibition of IRE1α endoribonuclease activity or downstream XBP1 modestly enhanced Cd-induced apoptosis. In vivo, administration with rapamycin suppressed activation of mTORC1 and JNK, but not eIF2α, in the kidney of Cd-treated mice. It was correlated with attenuation of tubular injury and apoptotic cell death in the tubules. These results elucidate dual regulation of Cd-induced renal injury by mTORC1 through selective induction of IRE1 signaling.
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Text Mining Data
mTORC1 — Raptor: " Knockdown of Raptor
, a positive regulator
, also had the similar effect "
mTORC1 — TSC2: " Knockdown of TSC2 , a negative regulator of mTORC1 , caused activation of mTORC1 and enhanced Cd induction of the IRE1-JNK pathway and apoptosis without affecting other UPR branches "
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