Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo

Erythropoietin (EPO), a member of the type 1 cytokine superfamily, plays a critical hormonal role regulating erythrocyte production as well as a paracrine/autocrine role in which locally produced EPO protects a wide variety of tissues from diverse injuries. Significantly, these functions are mediated by distinct receptors: hematopoiesis via the EPO receptor homodimer and tissue protection via a heterocomplex composed of the EPO receptor and CD131, the ␤ common receptor. In the present work, we have delimited tissueprotective domains within EPO to short peptide sequences. We demonstrate that helix B (amino acid residues 58 -82) of EPO, which faces the aqueous medium when EPO is bound to the receptor homodimer, is both neuroprotective in vitro and tissue protective in vivo in a variety of models, including ischemic stroke, diabetes-induced retinal edema, and peripheral nerve trauma. Remarkably, an 11-aa peptide composed of adjacent amino acids forming the aqueous face of helix B is also tissue protective, as confirmed by its therapeutic benefit in models of ischemic stroke and renal ischemia-reperfusion. Further, this peptide simulating the aqueous surface of helix B also exhibits EPO's trophic effects by accelerating wound healing and augmenting cognitive function in rodents. As anticipated, neither helix B nor the 11-aa peptide is erythropoietic in vitro or in vivo. Thus, the tissue-protective activities of EPO are mimicked by small, nonerythropoietic peptides that simulate a portion of EPO's three-dimensional structure.cognition ͉ cytoprotection ͉ excitotoxicity ͉ ischemia-reperfusion injury ͉ wound healing

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“…4). The degree of protection observed was similar to previous observations of EPO in this model (33).…”

Section: Resultssupporting

confidence: 80%

Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

Brines¹,

Patel

Villa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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272

279

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“…(C) Blinded scoring for acute tubular necrosis revealed better preservation of renal morphology after FG-4497 compared with Veh independent of the immunological constellation ( * , P Ͻ 0.05). confirmed that a number of genes previously identified as HIF-dependent are inducible in the kidney, including EPO, which has previously been demonstrated to be nephroprotective in renal ischemia-reperfusion models (30)(31)(32)(33), and HO-1, which has also been shown to improve short-and long-term graft function in the same rat model (34,35). In addition, HIF activation facilitates cellular anaerobic metabolism by inducing Glut-1 or enzymes involved in glycolysis.…”

Section: Discussionsupporting

confidence: 56%

Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model

Bernhardt

Göttmann

Doyon

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

131

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“…Recent findings revealed tissue-protective properties of EPO independent of its hematopoietic properties in a variety of organ systems suffering from ischemia, such as the heart, 5 brain, 6,7 liver, 8 kidney 9 and the striated muscle. 10 EPO initiates a multitude of EPO receptor-dependent and -independent cellular pathways, including the induction of anti-apoptotic genes 11 and anti-inflammatory molecules, 12 the increase of vascular endothelial growth factor (VEGF), as well as the production of vasodilative molecules such as nitric oxide (NO).…”

mentioning

confidence: 99%

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

Rezaeian

Wettstein

Egger

et al. 2010

Laboratory Investigation

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Recent findings have attested the protective effects of erythropoietin (EPO) in ischemically challenged organs. We therefore aimed at elaborating the underlying mechanism of EPO-mediated protection in musculocutaneous tissue undergoing persistent ischemia after acute injury. Mice were assigned to five experimental groups equipped with a randomly perfused flap fixed in a dorsal skinfold chamber, whereas the sixth group did not undergo flap preparation: EPO, L-Name, EPO and L-Name, EPO and bevacizumab, untreated flap, and nonischemic chamber (control). Intravital fluorescence microscopic analysis of microhemodynamics, apoptotic cell death, macromolecular leakage and angiogenesis was carried out over a 10-day period. Further, immunohistochemical analysis was used to study the protein expression of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF). Increased expression of eNOS in EPO-administered mice correlated with significant arteriolar dilation and thus increased blood flow resulting in a maintained functional capillary density (FCD) at day 10. In addition, EPO induced a VEGF upregulation, which was associated with newly formed capillaries. In addition, EPO was able to reduce ischemia-induced apoptotic cell death and finally to significantly reduce flap necrosis. In contrast, coadministration of L-Name abolished EPO-mediated tissue protection by abrogating the dilatory effect resulting in reduced FCD and tissue survival, without counteracting angiogenesis and apoptotic cell death, whereas additional administration of bevacizumab did not influence the beneficial effect of EPO on flap survival despite abrogating angiogenesis. Macromolecular leakage was found to be increased in all treatment groups. This study shows that EPO administration prevents musculocutaneous tissue from ischemic necrosis as a consequence of an eNOS-dependent arteriolar hyperperfusion maintaining capillary perfusion, thus representing a promising approach to pharmacologically protect ischemically challenged tissue.

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Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo

Cited by 185 publications

References 22 publications

Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model

Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage

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