Late administration of a novel EPO analogue in the presence of immunosuppressants protects the mouse kidney from ischaemia/reperfusion injury

Nimesh Patel1, Michael Brines2, Anthony Cerami2, Christoph Thiemermann1
1The William Harvey Research Institute, London, UK, 2Araim Pharmaceuticals Inc., New York, United States

Erythropoietin (EPO) is the major hormone stimulating the production and differentiation of red blood cells. EPO is used widely for treating anaemia of renal disease or anaemia induced by chemotherapy. EPO is beneficial in various models of ischaemia/reperfusion injury (IRI) such as stroke, myocardial infarction, hind-limb ischaemia, acute kidney injury, haemorrhagic shock and liver ischaemia. There are two biologically distinct functions of EPO through its interaction with two very different types of receptors: EPO receptor homodimer (erythropoiesis) and beta common heterocomplex (tissue protection). The novel peptide ARA290 has been modelled upon the 3D structure of the region of EPO presumed to bind to and initiate signalling of the beta common heterocomplex. Thirty-five male C57/B6 mice (20g) were subjected to 30 min bi-lateral renal ischeamia and 24 h reperfusion. ARA290 (10 μg/kg) was administered in saline 6 h after the onset of reperfusion. ARA290 significantly attenuated both the renal dysfunction and injury associated with renal IRI. Kidney transplantation is the best available therapy for patients with end-stage renal disease. Kidneys subjected to pre-retrieval warm ischaemia are at risk of developing IRI after transplantation, which is the most important antigen-independent negative factor associated with chronic allograph nephropathy. Forty “immunosuppressed” male C57/B6 mice (20g) were subjected to 30 min bi-lateral renal ischeamia and 48 h reperfusion. ARA290 (10 μg/kg) was administered in saline 6 h after the onset of reperfusion. A single administration of ARA290 6 h into reperfusion attenuates the increased renal dysfunction and injury caused by immunosuppressive therapy.