RESUMEN
BACKGROUND: Cellular stress is involved in ischemia/reperfusion- (I/R-) induced acute kidney injury (AKI). This study is aimed at investigating the effects of pretreatment with cholecalciferol on renal oxidative stress and endoplasmic reticulum (ER) stress during I/R-induced AKI. METHODS: I/R-induced AKI was established by cross-clamping renal pedicles for 90 minutes and then reperfusion. In the Chol + I/R group, mice were orally administered with three doses of cholecalciferol (25 µg/kg) at 1, 24, and 48 h before ischemia. Renal cellular stress and kidney injury were measured at different time points after reperfusion. RESULTS: I/R-induced AKI was alleviated in mice pretreated with cholecalciferol. In addition, I/R-induced renal cell apoptosis, as determined by TUNEL, was suppressed by cholecalciferol. Additional experiment showed that I/R-induced upregulation of renal GRP78 and CHOP was inhibited by cholecalciferol. I/R-induced renal IRE1α and eIF2α phosphorylation was attenuated by cholecalciferol. Moreover, I/R-induced renal GSH depletion, lipid peroxidation, and protein nitration were blocked in mice pretreated with cholecalciferol. I/R-induced upregulation of renal NADPH oxidases, such as p47phox, gp91phox, and nox4, was inhibited by cholecalciferol. I/R-induced upregulation of heme oxygenase- (HO-) 1, gshpx and gshrd, was attenuated in mice pretreated with cholecalciferol. CONCLUSIONS: Pretreatment with cholecalciferol protects against I/R-induced AKI partially through suppressing renal cellular stress response.
Asunto(s)
Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Colecalciferol/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Riñón/patología , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/complicaciones , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Chaperón BiP del Retículo Endoplásmico , Glutatión/metabolismo , Riñón/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones Endogámicos ICR , NADPH Oxidasas/metabolismo , Receptores de Calcitriol/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
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, 2.0â¯mg/kg). In the OCAâ¯+â¯LPS group, mice were orally pretreated with three doses of OCA (5â¯mg/kg) at 48, 24 and 1â¯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.