Farnesoid X receptor agonist obeticholic acid inhibits renal inflammation and oxidative stress during lipopolysaccharide-induced acute kidney injury.

Abstract

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.

• Authors: Jin-Bo Zhu, Shen Xu, Jun Li, Jin Song, Biao Luo, Ya-Ping Song, Zhi-Hui Zhang, Yuan-Hua Chen, Dong-Dong Xie, De-Xin Yu, De-Xiang Xu
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 838 Pg. 60-68 (Nov 05 2018) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 30196109 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• Lipopolysaccharides
• Receptors, Cytoplasmic and Nuclear
• obeticholic acid
• farnesoid X-activated receptor
• Chenodeoxycholic Acid

Topics

• Acute Kidney Injury (drug therapy, immunology, pathology)
• Administration, Oral
• Animals
• Chenodeoxycholic Acid (analogs & derivatives, pharmacology, therapeutic use)
• Disease Models, Animal
• Humans
• Kidney (drug effects, pathology)
• Lipopolysaccharides (immunology)
• Male
• Mice
• Mice, Inbred ICR
• Nephritis (drug therapy, immunology, pathology)
• Oxidative Stress (drug effects)
• Receptors, Cytoplasmic and Nuclear (agonists, metabolism)