Farnesoid X receptor ligand prevents cisplatin-induced kidney injury by enhancing small heterodimer partner.
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.
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Eun Hui
EH
Bae
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Hong Sang
HS
Choi
Department of Physiology, Chonnam National University Medical School, Gwangju, Korea.
Soo Yeon
SY
Joo
Department of Physiology, Chonnam National University Medical School, Gwangju, Korea.
In Jin
IJ
Kim
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Chang Seong
CS
Kim
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Joon Seok
JS
Choi
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Seong Kwon
SK
Ma
Department of Physiology, Chonnam National University Medical School, Gwangju, Korea.
Jongun
J
Lee
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Soo Wan
SW
Kim
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000517:prevention & control*; D000704:Analysis of Variance; D000818:Animals; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002945:Cisplatin / Q000009:adverse effects*; D017931:DNA Primers / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D002945:Cisplatin; D017931:DNA Primers; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D053773:Transforming Growth Factor beta1; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C464660:obeticholic acid