title: Amelioration of lipopolysaccharide-induced acute kidney injury by erythropoietin: involvement of mitochondria-regulated apoptosis.
abstract: Sepsis remains the most important cause of acute kidney injury (AKI) in critically ill patients and is an independent predictor of poor outcome. The administration of lipopolysaccharide (LPS) to animals reproduces most of the clinical features of sepsis, including AKI, a condition associated with renal cellular dysfunction and apoptosis. Erythropoietin (EPO) is a well known cytoprotective multifunctional hormone, which exerts anti-inflammatory, anti-oxidant, anti-apoptotic and angiogenic effects in several tissues. The aim of this study was to evaluate the underlying mechanisms of EPO renoprotection through the expression of the EPO receptor (EPO-R) and the modulation of the intrinsic apoptotic pathway in LPS-induced AKI. Male inbred Balb/c mice were divided in four experimental groups: Control, LPS (8 mg/kg i.p.), EPO (3000 IU sc) and LPS+EPO. Assessment of renal function, histological examination, TUNEL in situ assay, immunohistochemistry and Western blottings of caspase-3, Bax, Bcl-xL, EPO-R and Cytochrome c were performed at 24h post treatment. LPS+EPO treatment significantly improved renal function and ameliorated histopathological injury when compared to the LPS treated group. Results showed that EPO treatment attenuates renal tubular apoptosis through: (a) the overexpression of EPO-R in tubular interstitial cells, (b) the reduction of Bax/Bcl-xL ratio, (c) the inhibition Cytochrome c release into the cytosol and (d) the decrease of the active caspase-3 expression. This study suggests that EPO exerts renoprotection on an experimental model of LPS-induced AKI. EPO induced renoprotection involves an anti-apoptotic effect through the expression of EPO-R and the regulation of the mitochondrial apoptotic pathway.
authors.affiliation: Department of Biochemistry, School of Medicine, National Northeast University, Moreno 1240 (3400), Corrientes, Argentina; CONICET-SEGCyT, National Northeast University, Argentina.
authors.forename: Tania R
authors.initials: TR
authors.lastname: Stoyanoff
authors.affiliation: Department of Biochemistry, School of Medicine, National Northeast University, Moreno 1240 (3400), Corrientes, Argentina; SEGCyT, National Northeast University, Argentina.
authors.forename: Juan S
authors.initials: JS
authors.lastname: Todaro
authors.affiliation: Department of Biochemistry, School of Medicine, National Northeast University, Moreno 1240 (3400), Corrientes, Argentina. Electronic address: vikyaguirre@yahoo.com.
authors.forename: María V
authors.initials: MV
authors.lastname: Aguirre
authors.affiliation: Department of Biochemistry, School of Medicine, National Northeast University, Moreno 1240 (3400), Corrientes, Argentina; CONICET, Argentina.
authors.forename: María C
authors.initials: MC
authors.lastname: Zimmermann
authors.affiliation: Department of Biochemistry, School of Medicine, National Northeast University, Moreno 1240 (3400), Corrientes, Argentina; CONICET, Argentina.
authors.forename: Nora C
authors.initials: NC
authors.lastname: Brandan
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003451:Cryoprotective Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000378:metabolism*
chemical_list: D003451:Cryoprotective Agents; D008070:Lipopolysaccharides; D017467:Receptors, Erythropoietin; D004921:Erythropoietin
keywords: Apoptosis; Cytochrome c; EPO-R; Erythropoietin; LPS-induced AKI; Renoprotection