Targeting the innate repair receptor axis <i>via</i> erythropoietin or pyroglutamate helix B surface peptide attenuates hemolytic-uremic syndrome in mice.
Dennhardt. Sophie S; Pirschel. Wiebke W; Wissuwa. Bianka B; Imhof. Diana D; Daniel. Christoph C; Kielstein. Jan T JT; Hennig-Pauka. Isabel I; Amann. Kerstin K; Gunzer. Florian F; Coldewey. Sina M SM
Key Findings
- People and animals with hemolytic‑uremic syndrome (HUS) naturally have higher blood levels of EPO, suggesting the hormone is involved in the disease.
- Giving either regular EPO or the peptide ARA‑290 improved 7‑day survival and reduced kidney oxidative stress in mice with HUS.
- Only ARA‑290 (pHBSP) lowered nitrosative stress and prevented kidney cell dedifferentiation, without causing clotting or other side effects.
Practical Outcomes
- The study hints that ARA‑290 could be repurposed to protect kidneys and improve survival in HUS, but it does not provide a dosage, safety profile for humans, or clear benefits for kidney function. For biohackers, it’s an interesting proof‑of‑concept rather than a ready protocol to try.
Summary
In a mouse study, giving the EPO‑like peptide ARA‑290 (also called pHBSP) helped mice survive a severe kidney disease caused by Shiga toxin, mainly by lowering oxidative stress in the kidneys. It didn’t fix the kidney damage itself, and the research is still early, so it’s not a ready‑to‑use treatment for most people.
Abstract
Hemolytic-uremic syndrome (HUS) can occur as a systemic complication of infections with Shiga toxin (Stx)-producing <i>Escherichia coli</i> 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 <i>via</i> 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.
Study Information
pubmed
2022
2022-09-23T00:00:00.000Z
10.3389/fimmu.2022.1010882
4
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