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.
Highlights
Cisplatin is one of the most frequently used chemotherapeutic agents against solid tumors [1]
We investigated whether Farnesoid X receptor (FXR) ligand could attenuate fibrosis, inflammation and apoptosis in cisplatin-induced kidney injury
small heterodimer partner (SHP) expression was inhibited in cisplatin-induced kidney injury in mice; this effect was attenuated by FXR ligand (Figure 2A)
Summary
Cisplatin is one of the most frequently used chemotherapeutic agents against solid tumors [1]. We have demonstrated that cisplatin-induced nephrotoxicity is associated with the activation of apoptosis, inflammation and fibrosis pathways [2]. A single injection of cisplatin may induce renal epithelial cell damage, epithelial-to-mesenchymal transition (EMT), and progressive interstitial fibrosis, along with an upregulation of transforming growth factor-b1 (TGF-b1) [3,4]. Cisplatin may activate proapoptotic genes and repress anti-apoptotic genes by transcriptional regulation [5]. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that functions as an endogenous sensor for bile acids [6]. The most potent natural activator of human FXR seems to be chenodeoxycholic acid (CDCA). 6-Ethyl chenodeoxycholic acid (6ECDCA), which increases FXR affinity by substitution with alkyl groups is a more potent FXR agonist than CDCA [7]. The molecular basis of this phenomenon has not been defined
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