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.
Highlights
Acute kidney injury (AKI) and chronic transplant nephropathy are defined by a progressive functional deterioration of the kidney that is associated with interstitial fibrosis, tubular atrophy and glomerulosclerosis leading to late renal allograft failure
To gain a better insight into the signaling pathways involved in the tissue-protective and/or antiinflammatory effects of pHBSP, we investigated the effects of pHBSP on signaling pathways known to play a role in tissue injury/survival and/or inflammation
Because this peptide is based on helix B of EPO, we carried out these mechanistic studies in kidney samples from animals treated with EPO, in the hope to find common signaling events that contribute to the observed beneficial effects of pHBSP in vivo
Summary
Acute kidney injury (AKI) and chronic transplant nephropathy are defined by a progressive functional deterioration of the kidney that is associated with interstitial fibrosis, tubular atrophy and glomerulosclerosis leading to late renal allograft failure. In vivo models of renal IRI have extensively demonstrated the evolution of AKI and the consequent long-term chronic lesions that mimic those demonstrated in chronic transplant nephropathy [1]. Fractional excretion of sodium together with glomerular filtration rate is used to monitor tubular as well as glomerular function. Deterioration in both these markers is indicative of AKI and has been shown to change during the evolution of AKI [4]. Patients have to be treated during the early phases of the evolution of AKI
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