title: Activation of liver X receptors inhibits cadmium-induced apoptosis of human renal proximal tubular cells.
abstract: Liver X receptors (LXRs) including LXRα and LXRβ are members of the nuclear receptor superfamily of ligand-activated transcription factors, which are expressed in high metabolic organs such as the liver, kidney, and adipose tissue. LXRs have been shown to act as antioxidants and anti-inflammatory in several organs. The present study investigated the effects of LXR activation on cadmium-induced cell death in renal proximal tubular cells. Treating human renal proximal tubular cells, HK-2 cells, with 20μM CdCl2 for 24h led to cell death via apoptosis but not necrosis. Interestingly, pretreating HK-2 cells with T0901317, a LXR agonist, significantly inhibited the apoptotic cell death induced by CdCl2. The protective effect of T0901317 was eliminated by incubation with fenofibrate, a LXR antagonist, indicating that the effect of T0901317 on cadmium-induced apoptotic cell death was mediated by LXR activation. In addition, the effect of CdCl2 was attenuated by a reactive oxygen species (ROS) scavenger, N-acetyl-l-cysteine (NAC). An increase in ROS induced by CdCl2 was mediated by inhibition of catalase but not superoxide dismutase (SOD) which was attenuated by T0901317. Western blot analysis revealed that CdCl2 stimulated expression of c-jun N-terminal kinase (JNK) phosphorylation and the stimulation were inhibited by NAC, indicating the induction of JNK phosphorylation was stimulated following ROS production. Moreover, the increases of ROS and JNK phosphorylation induced by CdCl2 were attenuated by LXR activation. This study provides the first evidence to show LXR activation reduces cadmium-induced apoptotic cell death of human renal proximal tubular cells by inhibition of ROS production and JNK activation.
authors.affiliation: Toxicology Program, Faculty of Science, Mahidol University, Bankok, Thailand.
authors.forename: Somsak
authors.initials: S
authors.lastname: Fongsupa
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Rangsit University, Pathumthani, Thailand.
authors.forename: Sirima
authors.initials: S
authors.lastname: Soodvilai
authors.affiliation: Research Center of Transport Proteins for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Chatchai
authors.initials: C
authors.lastname: Muanprasat
authors.affiliation: Research Center of Transport Proteins for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Varanuj
authors.initials: V
authors.lastname: Chatsudthipong
authors.affiliation: Research Center of Transport Proteins for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; Center of Excellence on Environmental Health and Toxicology, Ministry of Education, Bangkok, Thailand. Electronic address: sunhapas.soo@mahidol.ac.th.
authors.forename: Sunhapas
authors.initials: S
authors.lastname: Soodvilai
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D019256:Cadmium Chloride / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D000071518:Liver X Receptors; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D017382:Reactive Oxygen Species; D048670:MAP Kinase Kinase 4; D019256:Cadmium Chloride
keywords: Catalase; JNK; Kidney; Reactive oxidative species