cibinetide and Reperfusion-Injury

The protective, nonerythropoietic effects of erythropoietin (EPO) have become evident in preclinical models in renal ischaemia/reperfusion injury and kidney transplantation. However, four recently published clinical trials using high-dose EPO treatment following renal transplantation did not reveal any protective effect for short-term renal function and even reported an increased risk of thrombosis. This review focusses on the current status of protective pathways mediated by EPO, the safety concerns using high EPO dosage and discusses the discrepancies between pre-clinical and clinical studies. The protective effects are mediated by binding of EPO to a heteromeric receptor complex consisting of two β-common receptors and two EPO receptors. An important role for the activation of endothelial nitric oxide synthase is proposed. EPO-mediated cytoprotection still has enormous potential. However, only nonerythropoietic EPO derivatives may induce protection without increasing the risk of cardiovascular events. In preclinical models, nonerythropoietic EPO derivatives, such as carbamoylated EPO and ARA290, have been tested. These EPO derivatives improve renal function and do not affect erythropoiesis. Therefore, nonerythropoietic EPO derivatives may be able to render EPO-mediated cytoprotection useful and beneficial for clinical transplantation.

Topics: Animals; Cardiovascular Diseases; Cytoprotection; Erythropoietin; Hematinics; Humans; Kidney; Kidney Transplantation; Nitric Oxide Synthase Type III; Oligopeptides; Receptors, Erythropoietin; Recombinant Proteins; Reperfusion Injury; Risk Factors; Translational Research, Biomedical

The goal of this study was to analyze the protective role of ARA290 in early renal allograft injury by using a rat model of renal allograft.. Lewis rats were divided into 3 groups: sham, University of Wisconsin solution (UW), and ARA290. A rat model of renal allograft was established by anastomosis using a titanium ring pin stapler. The kidneys were removed 24 hours after transplantation to accomplish the following: (1) examine the protective effect of ARA290 on renal morphology and function; (2) investigate the underlying mechanism by determining the binding affinity of nuclear factor-κB (NF-κB) to DNA by using an electrophoretic mobility shift assay; (3) observe the effect of ARA290 on macrophage infiltration using immunohistochemistry; and (4) detect messenger RNA (mRNA) expression of inflammatory mediators by using reverse transcriptase polymerase chain reaction.. Serum creatinine and blood urea nitrogen levels in the ARA290 group were significantly lower than those in the UW group. Kidney tissue samples from the UW group exhibited morphologic abnormalities and marked macrophage infiltration compared with those in the sham group. In the ARA290 group, renal morphology was greatly improved with decreased macrophage infiltration. The binding affinity of NF-κB to DNA in the ARA290 group was markedly lower than that in the UW and sham groups. The mRNA expression of NF-κB downstream effectors (monocyte chemotactic protein-1; regulated on activation, normal T cell expressed and secreted; intercellular adhesion molecule-1; and vascular cell adhesion molecular-1) was significantly downregulated in the ARA290 group compared with that in the UW group.. ARA290 protects against early renal allograft injury in rats by reducing macrophage infiltration, improving renal morphology, inhibiting mRNA expression of inflammatory mediators, and weakening the binding affinity of NF-κB to DNA.

Topics: Acute Kidney Injury; Animals; Kidney; Kidney Transplantation; Male; NF-kappa B; Oligopeptides; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Reperfusion Injury; Tissue and Organ Harvesting; Transplantation, Homologous

ARA290 is a non-erythropoietic EPO derivative which only binds to the cytoprotective receptor complex (EPOR2-βcR2) consisting of two EPO-receptors (EPOR) and two β common receptors (βcR). ARA290 is renoprotective in renal ischemia/reperfusion (I/R). In a renal I/R model we focussed on timing of post-reperfusional administration of ARA290. Furthermore, we investigated the anti-inflammatory properties of ARA290.. Twenty-six male Lewis/HanHsd rats were exposed to unilateral ischemia for 30 minutes, with subsequent removal of the contralateral kidney. Post-reperfusion, ARA290 was administered early (one hour), late (four hours) or repetitive (one and four hours). Saline was used as vehicle treatment. Rats were sacrificed after three days.. Early ARA290 treatment improved renal function. Late- or repetitive treatment tended to improve clinical markers. Furthermore, early ARA290 treatment reduced renal inflammation and acute kidney injury at three days post-reperfusion. Late- or repetitive treatment did not affect inflammation or acute kidney injury.. ARA290 attenuated renal ischemia/reperfusion injury. This study showed the anti-inflammatory effect of ARA290 and suggests early administration in the post-reperfusional phase is most effective. ARA290 is a candidate drug for protection against ischemic injury following renal transplantation.

Topics: Acute Kidney Injury; Animals; Base Sequence; DNA Primers; Inflammation; Kidney; Male; Oligopeptides; Rats; Rats, Inbred Lew; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction

In contrast with various pre-clinical studies, recent clinical trials suggest that high dose erythropoietin (EPO) treatment following kidney transplantation does not improve short-term outcome and that it even increases the risk of thrombotic events. ARA290 is a non-erythropoietic EPO derivative and does not increase the risk of cardiovascular events, but potentially has cytoprotective capacities in prevention of renal ischemia/reperfusion injury.. Eight female Dutch Landrace pigs were exposed to unilateral renal ischemia for 45 minutes with simultaneous cannulation of the ureter of the ischemic kidney. ARA290 or saline was administered by an intravenous injection at 0, 2, 4 and 6 hours post-reperfusion. The animals were sacrificed seven days post-reperfusion.. ARA290 increased glomerular filtration rate during the observation period of seven days. Furthermore, ARA290 tended to reduce MCP-1 and IL-6 expression 15 minutes post-reperfusion. Seven days post-reperfusion ARA290 reduced interstitial fibrosis.. The improvement in renal function following renal ischemia/reperfusion and reduced structural damage observed in this study by ARA290 warrants further investigation towards clinical application.

Topics: Animals; DNA Primers; Female; Glomerular Filtration Rate; Kidney; Kidney Transplantation; Nitric Oxide Synthase; Oligopeptides; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Swine