title: Delayed administration of pyroglutamate helix B surface peptide (pHBSP), a novel nonerythropoietic analog of erythropoietin, attenuates acute kidney injury.
abstract: In preclinical studies, erythropoietin (EPO) reduces ischemia-reperfusion-associated tissue injury (for example, stroke, myocardial infarction, acute kidney injury, hemorrhagic shock and liver ischemia). It has been proposed that the erythropoietic effects of EPO are mediated by the classic EPO receptor homodimer, whereas the tissue-protective effects are mediated by a hetero-complex between the EPO receptor monomer and the β-common receptor (termed "tissue-protective receptor"). Here, we investigate the effects of a novel, selective-ligand of the tissue-protective receptor (pyroglutamate helix B surface peptide [pHBSP]) in a rodent model of acute kidney injury/dysfunction. Administration of pHBSP (10 μg/kg intraperitoneally [i.p.] 6 h into reperfusion) or EPO (1,000 IU/kg i.p. 4 h into reperfusion) to rats subjected to 30 min ischemia and 48 h reperfusion resulted in significant attenuation of renal and tubular dysfunction. Both pHBSP and EPO enhanced the phosphorylation of Akt (activation) and glycogen synthase kinase 3β (inhibition) in the rat kidney after ischemia-reperfusion, resulting in prevention of the activation of nuclear factor-κB (reduction in nuclear translocation of p65). Interestingly, the phosphorylation of endothelial nitric oxide synthase was enhanced by EPO and, to a much lesser extent, by pHBSP, suggesting that the signaling pathways activated by EPO and pHBSP may not be identical.
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, The William Harvey Research Institute, London, UK. n.s.patel@qmul.ac.uk
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Kerr-Peterson
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Mara
authors.initials: M
authors.lastname: Rogazzo
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Wood
authors.forename: Florence L
authors.initials: FL
authors.lastname: Johnson
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Yaqoob
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D051152:Clusterin / Q000097:blood; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007678:Kidney Glomerulus / Q000187:drug effects / Q000503:physiopathology; D007684:Kidney Tubules / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage*; D053495:Osteopontin / Q000097:blood; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D051152:Clusterin; D016328:NF-kappa B; D009842:Oligopeptides; D053495:Osteopontin; C576178:cibinetide; D052250:Nitric Oxide Synthase Type III; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3