RESUMEN
Erythropoietin (EPO) production in the kidney is regulated by the oxygen-sensing transcription factor HIF-1α, which is degraded under normoxic conditions by HIF-prolyl hydroxylase (HIF-PHD). Inhibition of HIF-PHD by roxadustat leads to increased EPO production, better iron absorption, and amelioration of anemia in chronic kidney disease (CKD).
Asunto(s)
Anemia/terapia , Glicina/análogos & derivados , Factor 1 Inducible por Hipoxia/metabolismo , Isoquinolinas/uso terapéutico , Anemia/metabolismo , Glicina/uso terapéutico , Humanos , Factor 1 Inducible por Hipoxia/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Prolil Hidroxilasas/efectos de los fármacos , Prolil Hidroxilasas/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismoRESUMEN
The epidemic of obesity and its complications is rapidly increasing worldwide. Recent drug discoveries established the utility of prolyl hydroxylase domain (PHD) inhibitors as stabilizers of hypoxia-inducible factors (HIFs) in vivo, which are currently in human clinical studies for the treatment of anemia in chronic kidney disease (CKD). These studies suggest a role for PHD inhibitors in ameliorating obesity and hyperlipidemia. We hypothesized that HIF activation using a PHD inhibitor, JTZ-951, protects from obesity-related diseases in the white adipose tissue (WAT), liver, and kidney in mice fed with high-fat diet (HFD). Eight-week-old, C57BL/6J mice were fed with HFD for 20 weeks with or without JTZ-951(0.005%; mixed in chow). Body weight and plasma non-high-density lipoprotein (HDL) cholesterol levels were significantly lower in the JTZ-951 group as compared with the vehicle group. PHD inhibition improved liver steatosis, macrophage infiltration into WAT and adipocyte fibrosis. In the kidney, PHD inhibition reduced albuminuria. Histologically, the number of F4/80- positive infiltrating macrophages and mesangial expansion were milder in the JTZ-951 group. Relative mRNA expression of adiponectin in WAT was higher in the JTZ-951-treated group and inversely correlated with hepatic steatosis score, adipocyte macrophage aggregation, and albuminuria. Activation of HIF ameliorates multiple obesity-related consequences in mice with HFD. The results of the present study offer the promising view that pharmacological PHD inhibition may be beneficial for the treatment of obesity-related diseases that can be ameliorated by weight loss.
Asunto(s)
Dieta Alta en Grasa , Glicinas N-Sustituídas/farmacología , Obesidad/metabolismo , Prolil Hidroxilasas/efectos de los fármacos , Piridinas/farmacología , Triazoles/farmacología , Tejido Adiposo Blanco/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Hígado Graso/metabolismo , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
PURPOSE: This study investigated the neuroprotective effect against photoreceptor cell death using prolyl-4-hydroxylases inhibitor (PHI), an HIF-1α stabilizer, in experimental retinal detachment (RD). METHODS: RD was created in Brown Norway rats by subretinal injection of 1% sodium hyaluronate. FG-4592 (a PHI, 25 mg/kg) or a vehicle was administered every 2 days with retro-orbital injection. Photoreceptor death was evaluated by TdT-dUTP terminal nick-end labeling (TUNEL) assay 3 days after RD and by the thickness of the outer nuclear layer 7 days after RD. The mitophagy-related markers Hypoxia Inducible Factor 1α (HIF-1α), BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), autophagy-related gene 5 (Atg5), microtubule-associated protein 1 light chain 3 beta (LC3B), and FUN14 domain containing 1 (FUNDC1) were detected by Western blot and immunofluorescence. Transmission electron microscopy was used to observe ultramicro-morphological changes. Mitochondrial damage was evaluated by the measurement of reactive oxygen species (ROS) by in situ ROS detection with dihydroethidium. RESULTS: The accumulation of HIF-1α and BNIP3 significantly increased after PHI treatment (P < 0.05), the pattern of Atg5 and LC3 changed, and FUNDC1 and LC3 were colocated. More autophagic vacuoles engulfing mitochondria were observed in transmission electron microscopy sections after PHI treatment when compared with the control. ROS significantly decreased in the PHI-treatment group (P < 0.05). This resulted in reduced TUNEL-positive photoreceptors 3 days after RD and an increased thickness of the outer nuclear layer 7 days after RD (P < 0.05). CONCLUSIONS: HIF-1α stabilization as a result of PHI treatment, along with the enhancement of mitophagy, could provide protection against photoreceptor injury following RD, which might be mediated by excessive ROS generation.