title: Erythropoietin attenuates renal and pulmonary injury in polymicrobial induced-sepsis through EPO-R, VEGF and VEGF-R2 modulation.
abstract: Sepsis remains the most important cause of acute kidney injury (AKI) and acute lung injury (ALI) in critically ill patients. The cecal ligation and puncture (CLP) model in experimental mice reproduces most of the clinical features of sepsis. Erythropoietin (EPO) is a well-known cytoprotective multifunctional hormone, which exerts anti-inflammatory, anti-oxidant, anti-apoptotic and pro-angiogenic effects in several tissues. The aim of this study was to evaluate the underlying mechanisms of EPO protection through the expression of the EPO/EPO receptor (EPO-R) and VEGF/VEF-R2 systems in kidneys and lungs of mice undergoing CLP-induced sepsis. Male inbred Balb/c mice were divided in three experimental groups: Sham, CLP, and CLP+EPO (3000IU/kg sc). Assessment of renal functional parameters, survival, histological examination, immunohistochemistry and/or Western blottings of EPO-R, VEGF and VEGF-R2 were performed at 18h post-surgery. Mice demonstrated AKI by elevation of serum creatinine and renal histologic damage. EPO treatment attenuates renal dysfunction and ameliorates kidney histopathologic changes. Additionally, EPO administration attenuates deleterious septic damage in renal cortex through the overexpression of EPO-R in tubular interstitial cells and the overexpression of the pair VEGF/VEGF-R2. Similarly CLP- induced ALI, as evidenced by parenchymal lung histopathologic alterations, was ameliorated through pulmonary EPO-R, VEGF and VEGF-R2 over expression suggesting and improvement in endothelial survival and functionality. This study demonstrates that EPO exerts protective effects in kidneys and lungs in mice with CLP-induced sepsis through the expression of EPO-R and the regulation of the VEGF/VEGF-R2 pair.
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina.
authors.forename: Mauro
authors.initials: M
authors.lastname: Heitrich
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina.
authors.forename: Daiana Maria de Los Ángeles
authors.initials: DM
authors.lastname: García
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina.
authors.forename: Tania Romina
authors.initials: TR
authors.lastname: Stoyanoff
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Rodríguez
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina.
authors.forename: Juan Santiago
authors.initials: JS
authors.lastname: Todaro
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina. Electronic address: mvaguirre@med.unne.edu.ar.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Aguirre
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy*; D055371:Acute Lung Injury / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001806:Blood Urea Nitrogen; D002432:Cecum / Q000473:pathology; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008026:Ligation; D008297:Male; D008807:Mice, Inbred BALB C; D011677:Punctures; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D018805:Sepsis / Q000382:microbiology*; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D017467:Receptors, Erythropoietin; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D003404:Creatinine; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Acute kidney injury (AKI); Acute lung injury (ALI); Cecal ligation and puncture (CLP); Erythropoietin (EPO); Sepsis