obeticholic-acid and Acute-Kidney-Injury

It is increasingly recognized that farnesoid X receptor (FXR) has anti-inflammatory and antioxidant activities. The present study investigated the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, on renal inflammation and oxidative stress in a model of sepsis-induced acute kidney injury. All mice except controls were intraperitoneally injected with lipopolysaccharide (LPS, 2.0 mg/kg). In the OCA + LPS group, mice were orally pretreated with three doses of OCA (5 mg/kg) at 48, 24 and 1 h before LPS injection. Interestingly, OCA pretreatment alleviated LPS-induced renal dysfunction and pathological damage. Moreover, OCA pretreatment repressed renal inflammatory cytokines and chemokines during LPS-induced acute kidney injury. In addition, OCA blocked nuclear translocation of nuclear factor kappa B (NF-κB) p65 and p50 subunits in tubular epithelial cells of renal cortex. Additional experiment showed that OCA pretreatment attenuated LPS-induced renal glutathione depletion, lipid peroxidation and protein nitration. Moreover, OCA pretreatment inhibited the upregulation of renal NADPH oxidase and inos genes during LPS-induced acute kidney injury. In conclusion, OCA pretreatment protects against sepsis-induced acute kidney injury through inhibiting renal inflammation and oxidative stress. These results provide evidence for roles of FXR as an important regulator of inflammation and oxidative stress in the kidney.

Topics: Acute Kidney Injury; Administration, Oral; Animals; Chenodeoxycholic Acid; Disease Models, Animal; Humans; Kidney; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Nephritis; Oxidative Stress; Receptors, Cytoplasmic and Nuclear

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.

Topics: Acute Kidney Injury; Analysis of Variance; Animals; Chenodeoxycholic Acid; Cisplatin; DNA Primers; Epithelial-Mesenchymal Transition; Immunoblotting; Immunoenzyme Techniques; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Receptors, Cytoplasmic and Nuclear; RNA Interference; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta1