Journal
CELL DEATH & DISEASE
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2016.78
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Funding
- National Natural Science Foundation of China (NSFC) [81172705, 81573181, 81402648, 81472997]
- NSFC Key Program [81130052]
- Early-stage Project of National Key Basic Research Program of China [2014CB560710]
- Natural Science Foundation of Fujian Province of China [2014J01372, 2015J01344]
- Science Foundation of Xiamen City [3502Z20140045]
- Science Foundation of Fujian Province [2014Y2004]
- Education Scientific Research Project of Young Teachers in Fujian Province [JA14004]
- Xiamen Municipal Bureau of Ocean and Fisheries [14PYY051SF04]
- Shanhai Fund Project [2013SH007]
- Xiamen University [CXB2014012]
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The heavy metal cadmium (Cd) is nephrotoxic. Recent studies show that autophagy plays an essential role in Cd-induced kidney injury. However, the mechanisms of Cd-induced kidney injury accompanied by autophagy are still obscure. In the present study, we first confirmed that Cd induced kidney damage and dysfunction, along with autophagy, both in vivo and in vitro. Then, we observed that cyclooxygenase-2 (COX-2) and the eIF2 alpha-ATF4 pathway of endoplasmic reticulum (ER) stress were induced by Cd in both kidney tissues and cultured cells. Further studies showed that inhibition of COX-2 with celecoxib or RNA interference (RNAi) inhibited the Cd-induced autophagy in kidney cells. In addition, blocking ER stress with 4-phenylbutyrate or RNAi partially counteracted COX-2 overexpression and autophagy induced by Cd, which suggested that ER stress was required for Cd-induced kidney autophagy. Significantly, our results showed that Cd activated ATF4 and induced its translocation to the nucleus. Knockdown of ATF4 inhibited Cd-induced COX-2 overexpression. While COX-2 overexpression is involved in renal dysfunction, there is no prior report on the role of COX-2 in autophagy regulation. The results of the current study suggest a novel molecular mechanism that the ER stress eIF2 alpha-ATF4 pathway-mediated COX-2 overexpression contributes to Cd-induced kidney autophagy and injury. The present study implies that COX-2 may be a potential target for therapy against Cd-induced nephrotoxicity.
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