ATF3 attenuates cyclosporin A-induced nephrotoxicity by downregulating CHOP in HK-2 cells.
Calcineurin inhibitors such as cyclosporin A (CsA) are widely used to treat organ transplantation-associated complications. However, CsA use is limited due to renal dysfunction. This study attempts to characterize the mechanism of CsA-induced nephrotoxicity using a human embryonic kidney cell line (HK-2). We performed microarray-based whole-genome expression analysis in HK-2 cells. CsA treatment induced the expression of endoplasmic reticulum (ER) stress-related and apoptosis-inducing genes at 6 and 24h, respectively, indicating that ER-stress predisposed the cells to apoptosis. G1 phase cell-cycle arrest was also observed via ER stress in CsA-treated cells. Furthermore, we found an inverse relationship between activating transcription factor 3 (ATF3), a stress-inducible protein, and C/EBP homologous protein (CHOP), an apoptosis-inducing protein. Moreover, when ATF3 knockdown cells were exposed to CsA, a prompt induction of CHOP was observed, which stimulated ROS production and induced cell death-related genes as compared to wild type. Taken together, our data demonstrate that ATF3 plays a pivotal role in the attenuation of CsA-induced nephrotoxicity by downregulating CHOP and ROS production mediated by ER stress.
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea.
Yong-Min
YM
Choi
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea.
Hey-Young
HY
Cho
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea.
Muhammad Ayaz
MA
Anwar
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea.
Han-Kyul
HK
Kim
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea.
Ji-Woong
JW
Kwon
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea. Electronic address: sangdunchoi@ajou.ac.kr.
Sangdun
S
Choi
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line / Q000187:drug effects; D016572:Cyclosporine / Q000633:toxicity*; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C497249:DDIT3 protein, human; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D016572:Cyclosporine
Activating transcription factor 3; C/EBP homologous protein; Cyclosporin A; HK-2 cell; Nephrotoxicity