Abstract
The farnesoid X receptor (FXR) is mainly expressed in liver, intestine and kidney. We investigated whether 6-ethyl chenodeoxycholic acid (6ECDCA), a semisynthetic derivative of chenodeoxycholic aicd (CDCA, an FXR ligand), protects against kidney injury and modulates small heterodimer partner (SHP) in cisplatin-induced kidney injury. Cisplatin inhibited SHP protein expression in the kidney of cisplatin-treated mice and human proximal tubular (HK2) cells; this effect was counteracted by FXR ligand. Hematoxylin and eosin staining revealed the presence of tubular casts, obstructions and dilatations in cisplatin-induced kidney injury, which was attenuated by FXR ligand. FXR ligand also attenuated protein expression of transforming growth factor-β1 (TGF-β1), Smad signaling, and the epithelial-to-mesenchymal transition process, inflammatory markers and cytokines, and apoptotic markers in cisplatin-treated mice. Cisplatin induced NF-κB activation in HK2 cell; this effect was attenuated by pretreatment with FXR ligand. In SHP knockdown by small interfering RNA, cisplatin-induced activation of TGF-β1, p-JNK and Bax/Bcl-2 ratio was not attenuated, while SHP overexpression and FXR ligand inhibited expression of these proteins in cisplatin-pretreated HK2 cells. In conclusion, FXR ligand, 6ECDCA prevents cisplatin-induced kidney injury, the underlying mechanism of which may be associated with anti-fibrotic, anti-inflammatory, and anti-apoptotic effects through SHP induction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Kidney Injury / chemically induced*
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Acute Kidney Injury / prevention & control*
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Analysis of Variance
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Animals
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Chenodeoxycholic Acid / analogs & derivatives*
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Chenodeoxycholic Acid / metabolism
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Chenodeoxycholic Acid / pharmacology
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Cisplatin / adverse effects*
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DNA Primers / genetics
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Epithelial-Mesenchymal Transition / drug effects
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Immunoblotting
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Immunoenzyme Techniques
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In Situ Nick-End Labeling
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Male
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Mice
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Mice, Inbred C57BL
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RNA Interference
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Signal Transduction / drug effects
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Transforming Growth Factor beta1 / metabolism
Substances
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DNA Primers
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RNA, Small Interfering
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Receptors, Cytoplasmic and Nuclear
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Transforming Growth Factor beta1
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nuclear receptor subfamily 0, group B, member 2
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obeticholic acid
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farnesoid X-activated receptor
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Chenodeoxycholic Acid
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Cisplatin
Grants and funding
This work was supported by the National Research Foundation of Korea (NRF) grant (MRC for Gene Regulation, 2011-0030132) funded by the Korea government (MSIP), by Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-20100008732), and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (2013R1A2A2A01067611). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.