Targeting the innate repair receptor axis via erythropoietin or pyroglutamate helix B surface peptide attenuates hemolytic-uremic syndrome in mice

Abstract

Hemolytic-uremic syndrome (HUS) can occur as a systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli and is characterized by microangiopathic hemolytic anemia and acute kidney injury. Hitherto, therapy has been limited to organ-supportive strategies. Erythropoietin (EPO) stimulates erythropoiesis and is approved for the treatment of certain forms of anemia, but not for HUS-associated hemolytic anemia. EPO and its non-hematopoietic analog pyroglutamate helix B surface peptide (pHBSP) have been shown to mediate tissue protection via an innate repair receptor (IRR) that is pharmacologically distinct from the erythropoiesis-mediating receptor (EPO-R). Here, we investigated the changes in endogenous EPO levels in patients with HUS and in piglets and mice subjected to preclinical HUS models. We found that endogenous EPO was elevated in plasma of humans, piglets, and mice with HUS, regardless of species and degree of anemia, suggesting that EPO signaling plays a role in HUS pathology. Therefore, we aimed to examine the therapeutic potential of EPO and pHBSP in mice with Stx-induced HUS. Administration of EPO or pHBSP improved 7-day survival and attenuated renal oxidative stress but did not significantly reduce renal dysfunction and injury in the employed model. pHBSP, but not EPO, attenuated renal nitrosative stress and reduced tubular dedifferentiation. In conclusion, targeting the EPO-R/IRR axis reduced mortality and renal oxidative stress in murine HUS without occurrence of thromboembolic complications or other adverse side effects. We therefore suggest that repurposing EPO for the treatment of patients with hemolytic anemia in HUS should be systematically investigated in future clinical trials.

HBSP improves kidney ischemia-reperfusion injury and promotes repair in properdin deficient mice via enhancing phagocytosis of tubular epithelial cells

“…In fact, the level of EPOR in P KO IR kidneys was still significantly higher than that in the WT control (1.7 0.8 vs. 0.1 0.0, P<0.05) after HBSP treatment. In addition, the expression of the heterodimer EPOR/bcR was greatly increased by IR injury in both genotypes and furthered by P KO (7.6×10 6 1.8×10 6 vs. 3.2×10 6 8.0×10 5 , P<0.05, Figure 2B). HBSP treatment significantly decreased the level of EPOR/bcR in the kidneys of P KO mice, but not in WT mice after IR.…”

“…Erythropoietin (EPO) receptors include the homodimer (EPOR) 2 initiating erythropoiesis and the heterodimer EPOR/bcR that delivers tissue protection only, thus also known as the innate repair receptor, without role in erythropoiesis (5). The function of EPOR/bcR was mainly discovered via its specific ligand EPOderived helix B surface peptide (HBSP) (6). HBSP attenuated cell death, inflammation and prevented progression of chronic fibrosis after kidney IR injury through multiple signaling pathways, including caspase 9/3, HSP70 and PI3K/Akt/FoxO3a signaling (7)(8)(9).…”