The role of liver X receptors (LXRs) in cadmium-induced nephrotoxicity
Liver X receptors (LXRs) including LXRα and LXRβ are members of the nuclear receptor superfamily of ligand-activated transcription factors, which are normally expressed in high metabolic organs such as liver, adipose tissues, and kidney. Recent evidence demonstrated that LXRs have anti-inflammatory...
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| 語言: | English |
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Mahidol University. Mahidol University Library and Knowledge Center
2023
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| 在線閱讀: | https://repository.li.mahidol.ac.th/handle/123456789/89747 |
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| 機構: | Mahidol University |
| 語言: | English |
| 總結: | Liver X receptors (LXRs) including LXRα and LXRβ are members of the nuclear receptor superfamily of ligand-activated transcription factors, which are normally expressed in high metabolic organs such as liver, adipose tissues, and kidney. Recent evidence demonstrated that LXRs have anti-inflammatory and antioxidant effects in tissues of several organs induced by oxidative agents. Cadmium induced cell death in several cell types is mediated by reactive oxidative species (ROS) generation and JNK activation. Therefore, this study was aimed to investigate the effects of LXR activation and the underlying mechanisms on the cadmium-induced cell death in human renal proximal tubular cells. The result showed that treatment of HK-2 cells with 20 µM CdCl2 for 24 hours led to cell death via apoptosis but not necrosis. Interestingly, pretreatment of HK-2 cells with T0901317, an LXR agonist, significantly inhibited the apoptotic cell death induced by CdCl2. The protective effect of T0901317 was eliminated by coincubation with fenofibrate, an 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). It was found that an increase in ROS induced by CdCl2 was mediated by inhibition of catalase (CAT) but not superoxide dismutase (SOD) which was attenuated by T0901317. In addition, the effect of CdCl2 on cell death was involved the up-regulated NAD(P)H dehydrogenase/ NADH: quinone oxidoreductase-1 (NQO1) expression which was blocked by NAC. This indicated that NQO1 induction by cadmium was downstream of ROS generation. Western blot analysis revealed that CdCl2 stimulated expression of c-jun N-terminal kinase (JNK) phosphorylation. The stimulation was inhibited by NAC, indicating the induction of JNK phosphorylation was downstream of ROS production. Moreover, the increases of ROS and JNK phosphorylation induced by CdCl2 were attenuated by LXR activation. In conclusion, this study provided the first evidence showing that LXR activation could reduce cadmium-induced apoptotic cell death of human renal proximal tubular cells by inhibition of ROS production and JNK activation. |
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