Delayed Administration of Pyroglutamate Helix B Surface Peptide (pHBSP), a Novel Nonerythropoietic Analog of Erythropoietin, Attenuates Acute Kidney Injury

Patel, Nimesh S. A.; Kerr-Peterson, Hannah L; Brines, Michael; Collino, Massimo; Rogazzo, Mara; Fantozzi, Roberto; Wood, Elizabeth G.; Johnson, Florence L.; Yaqoob, Muhammad; Cerami, Anthony; Thiemermann, Christoph

doi:10.2119/molmed.2012.00093

Cited by 39 publications

(45 citation statements)

References 68 publications

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“…35 Decreased levels of clusterin have been found (in general) in ESRD RBCs 14 and in the plasma of long-term ESRD survivors. 36 EPO can not only reduce clusterin's rise in plasma as previous studies shown, 37 but it can also negatively affect its association with RBCs in NR patients in vivo, as currently reported.…”

Section: Hypo-responsiveness To Epo Is Associated With a Modified Hsupporting

confidence: 72%

Pathophysiological aspects of red blood cells in end‐stage renal disease patients resistant to recombinant human erythropoietin therapy

Georgatzakou

Tzounakas

Kriebardis

et al. 2017

European J of Haematology

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Section: Hypo-responsiveness To Epo Is Associated With a Modified Hsupporting

confidence: 72%

Pathophysiological aspects of red blood cells in end‐stage renal disease patients resistant to recombinant human erythropoietin therapy

Georgatzakou

Tzounakas

Kriebardis

et al. 2017

European J of Haematology

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“…In the same study, protective capacities of prolonged pHBSP administration (s.c. daily for 10 days) in the healing of punch biopsy wounds have been provided. More recently, we demonstrated that a delayed administration (as late as 6 h into the reperfusion period) of a single dose of pHBSP was still able to improve the functional recovery of the kidney after the onset of reperfusion (after renal ischemia) in the rat (Patel et al, 2012). Similarly, van Rijt and colleagues have reported that the beneficial effects of pHBSP (when administered by an intravenous injection at 0, 2, 4 and 6 h postreperfusion) in a porcine model of renal I/R were associated with significant reductions of biomarkers of acute inflammation (interleukin-6, and monocyte chemotactic protein-1).…”

Section: Preclinical Studiesmentioning

confidence: 99%

“…The protective effects were time-dependent, as administration of pHBSP significantly attenuated the I/R induced rise in plasma parameters of kidney function only when administered at 6 h. In contrast, early administration of pHBSP at either 1 min or 30 min into reperfusion had no significant effect when compared to vehicle control mice. In the same model, a single dose administered with a 6 h delay produces sustained effects when evaluated 48 h later as shown by an increase in Akt phosphorylation, associated with an enhanced eNOS activation, thus resulting in protection against renal I/R injury (Patel et al, 2012).…”

Section: Molecular Mechanisms Of Tissue-protective Effectsmentioning

confidence: 99%

Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

Collino

Thiemermann

Cerami

et al. 2015

Pharmacology & Therapeutics

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Many disease processes activate a cellular stress response that initiates a cascade of inflammation and damage. However, this process also triggers a tissue protection and repair system mediated by locally-produced hyposialated erythropoietin (hsEPO). Although recombinant EPO is used widely for treating anemia, potential use of recombinant EPO for tissue-protection is limited by rises in hematocrit, platelet activation, and selectin expression resulting in a high risk of thrombosis. Importantly, the erythropoietic and tissue-protective effects of EPO are mediated by different receptors. Whereas EPO stimulates red cell progenitors by binding to an EPO receptor (EPOR) homodimer, a heterodimer receptor complex composed of EPOR and β common receptor (βcR) subunits, termed the innate repair receptor (IRR), activates tissue protection and repair. The IRR is typically not expressed by normal tissues, but instead is rapidly induced by injury or inflammation. Based on this understanding, EPO derivatives have been developed which selectively activate the IRR without interacting with the EPOR homodimer. The latest generation of specific ligands of the IRR includes an 11 amino acid peptide modeled from the three dimensional structure of the EPO in the region of helix B called pyroglutamate helix B surface peptide (pHBSP; ARA-290). Despite a short plasma half-life (~2min), pHBSP activates a molecular switch that triggers sustained biological effects that have been observed in a number of experimental animal models of disease and in clinical trials. This review summarizes pharmacokinetic and pharmacodynamic data and discusses the molecular mechanisms underlying the long-lasting effects of this short-lived peptide.

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“…Western blots were carried out as previously described [25]. Proteins were separated by 8% sodium dodecyl sulphate-polyacrylamide gel electrophoresis and transferred to polyvinyldenedifluoride membrane, which was then incubated with primary antibodies (goat anti-ICAM-1, mouse anti-phERK, rabbit anti-ERK, rabbit anti-iNOS, mouse anti-phAkt, rabbit anti Akt, goat anti-ph-eNOS, rabbit anti-eNOS, goat anti-CuZnSOD, rabbit anti-MnSOD).…”

Section: Western Blot Analysismentioning

confidence: 99%

Acute treatment with relaxin protects the kidney against ischaemia/reperfusion injury

Collino

Rogazzo

Pini

et al. 2013

J Cellular Molecular Medi

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Although recent preclinical and clinical studies have demonstrated that recombinant human relaxin (rhRLX) may have important therapeutic potential in acute heart failure and chronic kidney diseases, the effects of acute rhRLX administration against renal ischaemia/reperfusion (I/R) injury have never been investigated. Using a rat model of 1-hr bilateral renal artery occlusion followed by 6-hr reperfusion, we investigated the effects of rhRLX (5 μg/Kg i.v.) given both at the beginning and after 3 hrs of reperfusion. Acute rhRLX administration attenuated the functional renal injury (increase in serum urea and creatinine), glomerular dysfunction (decrease in creatinine clearance) and tubular dysfunction (increase in urinary excretion of N-acetyl-β-glucosaminidase) evoked by renal I/R. These beneficial effects were accompanied by a significant reduction in local lipid peroxidation, free radical-induced DNA damage and increase in the expression/activity of the endogenous antioxidant enzymes MnSOD and CuZnSOD superoxide dismutases (SOD). Furthermore, rhRLX administration attenuated the increase in leucocyte activation, as suggested by inhibition of myeloperoxidase activity, intercellular-adhesion-molecule-1 expression, interleukin (IL)-1β, IL-18 and tumour necrosis factor-α production as well as increase in IL-10 production. Interestingly, the reduced oxidative stress status and neutrophil activation here reported were associated with rhRLX-induced activation of endothelial nitric oxide synthase and up-regulation of inducible nitric oxide synthase, possibly secondary to activation of Akt and the extracellular signal-regulated protein kinase (ERK) 1/2, respectively. Thus, we report herein that rhRLX protects the kidney against I/R injury by a mechanism that involves changes in nitric oxide signalling pathway.

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Delayed Administration of Pyroglutamate Helix B Surface Peptide (pHBSP), a Novel Nonerythropoietic Analog of Erythropoietin, Attenuates Acute Kidney Injury

Cited by 39 publications

References 68 publications

Pathophysiological aspects of red blood cells in end‐stage renal disease patients resistant to recombinant human erythropoietin therapy

Pathophysiological aspects of red blood cells in end‐stage renal disease patients resistant to recombinant human erythropoietin therapy

Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

Acute treatment with relaxin protects the kidney against ischaemia/reperfusion injury

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