fg-4592 and Sepsis

Septic shock is a serious clinical syndrome leading to high mortality. A new anti-anemia drug Roxadustat (FG-4592) protected against cardiac injury and hypertension. However, its effect and mechanism on shock and cardiac dysfunction induced by sepsis require to be investigated.. C57BL/6j mice received FG-4592 (10 mg/kg/day) by i.p injection, followed by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) treatment. Mortality and shock status were monitored during the experiment. Cardiac function was assessed using echocardiography and serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) assay. TEM, COX-SDH staining and ATP production were used to evaluate mitochondrial function. A non-targeted metabolomic analysis was performed to evaluate the metabolic disorders.. Both pre- and post-treatment of FG-4592 could improve the survival rate in LPS- and CLP-induced sepsis mice with a better effect in pre-treated animals. Meanwhile, FG-4592 improved systolic blood pressure and body temperature drop in septic mice along with alleviated cardiac dysfunction (as shown by the restoration of decreased LVEF and LVFS and increased LDH and CK-MB) and inflammation. Interestingly, we observed that FG-4592 improved mitochondrial oxidative stress possibly by upregulating the anti-oxidative enzymes of SOD2 and HO-1. Furthermore, FG-4592 improved the energy supply and glycerophospholipid metabolism in cardiomyocytes, possibly through upregulating the HIF-1α-targeted genes of LDHA and PDK1 in glycolysis and CHK-α, respectively.. FG-4592 protected against mortality and shock in septic animals possibly by antagonizing mitochondrial oxidative stress and metabolic disorders.. This study provides a potential of FG-4592 as a novel drug for treating septic shock.

Topics: Animals; Energy Metabolism; Heart Diseases; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Oxidative Stress; Sepsis; Shock, Septic

Acute lung injury (ALI) is one of the most severe outcomes of sepsis which still waiting for effective treatment method. Roxadustat (FG-4592) which is often used for treatment of anemia in patients with chronic kidney disease (CKD), its affection on LPS-induced ALI haven't been evaluated. MH-S and MLE-12 cell injury and ALI mouse model was induced LPS. Several assays were used to explore the role of FG-4592 in reducing the damage caused by LPS. FG-4592 treatment significantly upregulated HIF-1α and HO-1 and strikingly attenuated inflammation in vivo and in vitro. Furthermore, septic mice overexpressing HIF-1α had high level of survival rate and lower expression of inflammatory factors while down-regulation can enhance the damage of LPS. HIF-1α has a protective effect on acute lung injury in LPS induced septic mice. FG-4592 treatment remarkably ameliorated the LPS-induced lung injury through the stabilization of HIF-1α. Besides the role in treating CKD anemia, the clinical use of FG-4592 also might be extended to ALI.

Topics: Acute Lung Injury; Animals; Cells, Cultured; Disease Models, Animal; Glycine; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Mice; Mice, Inbred BALB C; Sepsis