1. Farnesoid X receptor ligand prevents cisplatin-induced kidney injury by enhancing small heterodimer partner.
- Author
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Bae EH, Choi HS, Joo SY, Kim IJ, Kim CS, Choi JS, Ma SK, Lee J, and Kim SW
- Subjects
- Analysis of Variance, Animals, Chenodeoxycholic Acid metabolism, Chenodeoxycholic Acid pharmacology, DNA Primers genetics, Epithelial-Mesenchymal Transition drug effects, Immunoblotting, Immunoenzyme Techniques, In Situ Nick-End Labeling, Male, Mice, Mice, Inbred C57BL, RNA Interference, RNA, Small Interfering genetics, Real-Time Polymerase Chain Reaction, Signal Transduction drug effects, Transforming Growth Factor beta1 metabolism, Acute Kidney Injury chemically induced, Acute Kidney Injury prevention & control, Chenodeoxycholic Acid analogs & derivatives, Cisplatin adverse effects, Receptors, Cytoplasmic and Nuclear metabolism
- 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.
- Published
- 2014
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