title: Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the β-common receptor.
abstract: The β-common receptor (βcR) plays a pivotal role in the nonhematopoietic tissue-protective effects of erythropoietin (EPO). Here we determined whether EPO reduces the acute kidney injury (AKI) caused by sepsis and whether this effect is mediated by the βcR. In young (2 months old) C57BL/6 wild-type and βcR knockout mice, lipopolysaccharide caused a significant increase in serum urea and creatinine, hence AKI. This AKI was not associated with any overt morphological alterations in the kidney and was attenuated by EPO given 1 h after lipopolysaccharide in wild-type but not in βcR knockout mice. In the kidneys of endotoxemic wild-type mice, EPO enhanced the phosphorylation of Akt, glycogen synthase kinase-3β, and endothelial nitric oxide synthase, and inhibited the activation of nuclear factor-κB. All these effects of EPO were lost in βcR knockout mice. Since sepsis is more severe in older animals or patients, we tested whether EPO was renoprotective in 8-month-old wild-type and βcR knockout mice that underwent cecal ligation and puncture. These older mice developed AKI at 24 h, which was attenuated by EPO treatment 1 h post cecal ligation and puncture in wild-type mice but not in βcR knockout mice. Thus, activation of the βcR by EPO is essential for the observed reduction in AKI in either endotoxemic young mice or older mice with polymicrobial sepsis, and for the activation of well-known signaling pathways by EPO.
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK. s.m.coldewey@qmul.ac.uk
authors.forename: Sina M
authors.initials: SM
authors.lastname: Coldewey
authors.forename: Areeg I
authors.initials: AI
authors.lastname: Khan
authors.forename: Amar
authors.initials: A
authors.lastname: Kapoor
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Mara
authors.initials: M
authors.lastname: Rogazzo
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
authors.forename: Peter
authors.initials: P
authors.lastname: Hall
authors.forename: Michael
authors.initials: M
authors.lastname: Sheaff
authors.forename: Julius E
authors.initials: JE
authors.lastname: Kieswich
authors.forename: Muhammed M
authors.initials: MM
authors.lastname: Yaqoob
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002432:Cecum / Q000503:physiopathology; D053648:Cytokine Receptor Common beta Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D000072596:Hepatitis A Virus Cellular Receptor 1; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008026:Ligation; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018805:Sepsis / Q000139:chemically induced / Q000150:complications* / Q000209:etiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D053648:Cytokine Receptor Common beta Subunit; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D004921:Erythropoietin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3