RETRACTED: Local erythropoietin signaling enhances regeneration in peripheral axons

Toth, Cory; Martinez, José A.; Liu, W.Q.; Diggle, John; Guo, Gui Fang; Ramji, Noor; Mi, Ruifa; Höke, Ahmet; Zochodne, Douglas W.

doi:10.1016/j.neuroscience.2008.03.052

Cited by 59 publications

(46 citation statements)

References 66 publications

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“…Multifiber Motor and Sensory Conduction-Multifiber motor and sensory conduction studies were carried out in mice briefly anesthetized with isoflurane, using protocols previously reported (11). In brief, sciatic-tibial motor fibers were supramaximally stimulated at the sciatic notch and knee, and a compound muscle action potential was recorded (base line-peak amplitude) from the motor end plate of tibial innervated dorsal interosseous foot muscles.…”

Section: Methodsmentioning

confidence: 99%

Calnexin Deficiency Leads to Dysmyelination

Kraus

Groenendyk

Bedard

et al. 2010

Journal of Biological Chemistry

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Calnexin is a molecular chaperone and a component of the quality control of the secretory pathway. We have generated calnexin gene-deficient mice (cnx ؊/؊ ) and showed that calnexin deficiency leads to myelinopathy. Calnexin-deficient mice were viable with no discernible effects on other systems, including immune function, and instead they demonstrated dysmyelination as documented by reduced conductive velocity of nerve fibers and electron microscopy analysis of sciatic nerve and spinal cord. Myelin of the peripheral and central nervous systems of cnx ؊/؊ mice was disorganized and decompacted. There were no abnormalities in neuronal growth, no loss of neuronal fibers, and no change in fictive locomotor pattern in the absence of calnexin. This work reveals a previously unrecognized and important function of calnexin in myelination and provides new insights into the mechanisms responsible for myelin diseases.The endoplasmic reticulum (ER) 5 is the first compartment in the secretory pathway responsible for protein synthesis, posttranslational modification, and correct folding. The resident molecular chaperones ensure that only correctly folded proteins leave the ER. Calnexin is a type I ER membrane protein, a major component in assuring the quality control of the secretory pathway, and together with calreticulin and the oxidoreductase ERp57, it promotes the correct folding of newly synthesized glycoproteins (2). Calnexin and calreticulin bind monoglucosylated carbohydrate on newly synthesized glycoproteins, whereas ERp57 catalyzes rearrangements of disulfide bonds within the calnexin/calreticulin substrate proteins (2). Despite its ubiquitous expression, the absence of calnexin has a different effect in different organisms. Calnexin deficiency is lethal in Schizosaccharomyces pombe but not in Saccharomyces cerevisiae (3), Dictyostelium (4, 5), or Caenorhabditis elegans (6, 7). The loss of calnexin affects phagocytosis in Dictyostelium (4, 5) and promotes necrotic cell death in C. elegans (7). It has been reported that deletion of the calnexin gene in a mouse results in early postnatal death (1), and thus the molecular consequences of calnexin deficiency could not be studied.Here we show that calnexin deficiency in the mouse did not result in early postnatal death (1). These animals developed myelinopathy with no discernible effects on other systems, including immune function. The phenotype was linked to slow nerve conduction velocities in the absence of calnexin with evidence of peripheral axon dysmyelination. The dysmyelinating phenotype described here underscores the emerging importance of calnexin and ER-associated pathways as contributors to these severe neurological disorders.

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Section: Methodsmentioning

confidence: 99%

Calnexin Deficiency Leads to Dysmyelination

Kraus

Groenendyk

Bedard

et al. 2010

Journal of Biological Chemistry

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“…There are EPO receptors (EpoRs) widely distributed throughout a number of tissue types (48). The discovery that EpoRs are expressed in glomerular, mesangial, and tubular epithelial cells in human, rat, and mouse kidneys have prompted studies of the effects of EPO in small-rodent models of AKI (41,44). Such studies have shown that EPO not only stimulates erythropoiesis but also has antiinflammatory properties, as well as exerting the following effects (7,19,21,38): reducing apoptosis, oxidative stress, and lipid peroxidation; promoting renal tubular cell regeneration, vascular regeneration, and neoangiogenesis; mobilizing endothelial progenitor cells; and upregulating eNOS expression.…”

mentioning

confidence: 99%

“…Such studies have shown that EPO not only stimulates erythropoiesis but also has antiinflammatory properties, as well as exerting the following effects (7,19,21,38): reducing apoptosis, oxidative stress, and lipid peroxidation; promoting renal tubular cell regeneration, vascular regeneration, and neoangiogenesis; mobilizing endothelial progenitor cells; and upregulating eNOS expression. It is also known that EPO mediates neuroprotection against axonopathy and apoptosis in the peripheral nervous system by inhibiting NF-B activation, indicating rescue from an injury phenotype (44).…”

mentioning

confidence: 99%

Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase

Souza

Volpini

Shimizu

et al. 2012

American Journal of Physiology-Renal Physiology

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de Souza ACCP, Volpini RA, Shimizu MH, Sanches TR, Camara NOS, Semedo P, Rodrigues CE, Seguro AC, Andrade L. Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting nuclear factor-B and upregulating endothelial nitric oxide synthase. Am J Physiol Renal Physiol 302: F1045-F1054, 2012. First published January 11, 2012 doi:10.1152/ajprenal.00148.2011.-The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-B activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLPϩEPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-L-arginine methyl ester (L-NAME) simultaneously with EPO administration (CLPϩEPOϩL-NAME). A fifth group (CLPϩEPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLPϩEPO rats presented significantly higher inulin clearance than did CLP and CLPϩEPOϩL-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLPϩEPO rats; and inulin clearance was significantly higher in CLPϩEPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLPϩEPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-␣ activation, NF-B activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-B downregulation.THE MORTALITY RATES OF SEPSIS and septic shock remain unacceptably high and have not changed in several decades (5,6,26,30). Acute kidney injury (AKI) occurs in ϳ50% of patients with sepsis (5, 30). In such patients, the development of AKI is predictive of a poor outcome, and the consequent mortality has been reported to be as high as 70% (5). Despite improved strategies for supporting vital organs and resuscitating patients, the incidence and mortality rates of septic AKI remain quite high (5, 6). The prevention of kidney injury in intensive care settings continues to represent a great challenge.It has been shown that NF-B mediates the transcription of a large number of genes, the products of which are known to play important roles in septic pathophysiology (24, 31). Mice deficient in those NF-B-dependent genes are resistant to the development of septic shock and to sepsis-related mortality (31). More importantly, blockade of the NF-B pathway corr...

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“…rHu-EPO may indirectly mediate neuroprotection by restoring the blood supply to the injured tissue or acts directly over the neurons by activating multiple molecular signaling pathways. The rHu-EPO molecule positively modulates the expression of antioxidant enzymes and reduces nitric oxide mediated formation of free radicals; by a mechanism involving JAK2 [27] and the nuclear factor NFkB [28]. Its antioxidant action is also sustained by restoring the cytosolic catalase and glutathione peroxidase activities in erythrocytes, which protects against the oxidative stress by reducing lipid peroxidation [29] and also EPO plays an important role in protecting against brain ischemia/reperfusion through inhibiting lipid peroxidation and decreasing blood brain barrier (BBB) disruption [30].…”

Section: Brain Protection By Erythropoietinmentioning

confidence: 99%

Neuro-EPO by Nasal Route as a Neuroprotective Therapy in Brain Ischemia

Bretón¹

2012

Acute Ischemic Stroke

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RETRACTED: Local erythropoietin signaling enhances regeneration in peripheral axons

Cited by 59 publications

References 66 publications

Calnexin Deficiency Leads to Dysmyelination

Calnexin Deficiency Leads to Dysmyelination

Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase

Neuro-EPO by Nasal Route as a Neuroprotective Therapy in Brain Ischemia

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