Unravelling the therapeutic potential of erythropoietin signaling in hemolytic-uremic syndrome in mice : a preclinical work-up from model establishment to an interventional study

Typical hemolytic-uremic syndrome (HUS) occurs as a severe complication of an infection with enterohemorrhagic Escherichia coli (EHEC) and is one of the major causes of acute and chronic renal failure in children. HUS is clinically characterized by a symptom triad comprised of acute kidney injury (AKI), microangiopathic hemolytic anemia and thrombocytopenia. There is no approved specific therapy, intensive care is provided supportively. Erythropoietin (EPO), a hematopoietic hormone, confers tissue-protective effects that attenuated AKI in several other conditions such as sepsis. The tissue-protective effects of EPO are mediated via a heteromer of the EPO receptor (EPO-R) and the β-common receptor. This receptor can also be selectively activated by non-hematopoietic structure analogs of EPO such as pyroglutamate helix B surface peptide (pHBSP). The overall objective of this thesis was the preclinical assessment of the potential of EPO and pHBSP in the treatment of HUS. Firstly, two murine models of HUS have been established and extensively characterized by laboratory chemistry as well as histology and immunohistochemistry (manuscript I). In the following manuscript, EPO plasma levels of different species with HUS (humans, pigs, mice) were measured and an interventional study with EPO and pHBSP was performed applying the subacute model of HUS (manuscript II). Within the framework of this thesis, two relevant murine models suitable for the performance of preclinical interventional studies have been established. In the context of such a preclinical study, it was demonstrated that the modulation of the EPO/β-common-receptor axis attenuates disease severity in HUS. Thereby, this thesis provides the preclinical groundwork for further examinations in the repurposing of EPO and the implementation of pHBSP for the treatment of HUS.