Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury

Due to (i) the uremia-enhanced sepsis severity, (ii) the high prevalence of sepsis with pre-existing renal injury and (iii) the non-erythropoiesis immunomodulation of erythropoietin (EPO), EPO was tested in sepsis with pre-existing renal injury models with the retrospective exploration in patients....

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Autores principales:	Wiwat Chancharoenthana, Kanyarat Udompronpitak, Yolradee Manochantr, Piyawat Kantagowit, Ponthakorn Kaewkanha, Jiraporn Issara-Amphorn, Asada Leelahavanichkul
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cecal ligation and puncture erythropoietin LPS macrophages mortality rate sepsis Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/67626b2e53d945fda6d1da886504c00e
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spelling	oai:doaj.org-article:67626b2e53d945fda6d1da886504c00e2021-11-25T17:11:53ZRepurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury10.3390/cells101131332073-4409https://doaj.org/article/67626b2e53d945fda6d1da886504c00e2021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3133https://doaj.org/toc/2073-4409Due to (i) the uremia-enhanced sepsis severity, (ii) the high prevalence of sepsis with pre-existing renal injury and (iii) the non-erythropoiesis immunomodulation of erythropoietin (EPO), EPO was tested in sepsis with pre-existing renal injury models with the retrospective exploration in patients. Then, EPO was subcutaneously administered in mice with (i) cecal ligation and puncture (CLP) after renal injury including 5/6 nephrectomy (5/6Nx-CLP) and bilateral nephrectomy (BiNx-CLP) or sham surgery (sham-CLP) and (ii) lipopolysaccharide (LPS) injection, along with testing in macrophages. In patients, the data of EPO administration and the disease characteristics in patients with sepsis-induced acute kidney injury (sepsis-AKI) were evaluated. As such, increased endogenous EPO was demonstrated in all sepsis models, including BiNx-CLP despite the reduced liver erythropoietin receptor (EPOR), using Western blot analysis and gene expression, in liver (partly through hepatocyte apoptosis). A high-dose EPO, but not a low-dose, attenuated sepsis in mouse models as determined by mortality and serum inflammatory cytokines. Furthermore, EPO attenuated inflammatory responses in LPS-activated macrophages as determined by supernatant cytokines and the expression of several inflammatory genes (<i>iNOS</i>, <i>IL-1</i><i>β</i>, <i>STAT3</i> and <i>NF</i><i>κ</i><i>B</i>). In parallel, patients with sepsis-AKI who were treated with the high-dose EPO showed favorable outcomes, particularly the 29-day mortality rate. In conclusion, high-dose EPO attenuated sepsis with preconditioning renal injury in mice possibly through the macrophage anti-inflammatory effect, which might be beneficial in some patients.Wiwat ChancharoenthanaKanyarat UdompronpitakYolradee ManochantrPiyawat KantagowitPonthakorn KaewkanhaJiraporn Issara-AmphornAsada LeelahavanichkulMDPI AGarticlececal ligation and punctureerythropoietinLPSmacrophagesmortality ratesepsisBiology (General)QH301-705.5ENCells, Vol 10, Iss 3133, p 3133 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cecal ligation and puncture erythropoietin LPS macrophages mortality rate sepsis Biology (General) QH301-705.5
spellingShingle	cecal ligation and puncture erythropoietin LPS macrophages mortality rate sepsis Biology (General) QH301-705.5 Wiwat Chancharoenthana Kanyarat Udompronpitak Yolradee Manochantr Piyawat Kantagowit Ponthakorn Kaewkanha Jiraporn Issara-Amphorn Asada Leelahavanichkul Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury
description	Due to (i) the uremia-enhanced sepsis severity, (ii) the high prevalence of sepsis with pre-existing renal injury and (iii) the non-erythropoiesis immunomodulation of erythropoietin (EPO), EPO was tested in sepsis with pre-existing renal injury models with the retrospective exploration in patients. Then, EPO was subcutaneously administered in mice with (i) cecal ligation and puncture (CLP) after renal injury including 5/6 nephrectomy (5/6Nx-CLP) and bilateral nephrectomy (BiNx-CLP) or sham surgery (sham-CLP) and (ii) lipopolysaccharide (LPS) injection, along with testing in macrophages. In patients, the data of EPO administration and the disease characteristics in patients with sepsis-induced acute kidney injury (sepsis-AKI) were evaluated. As such, increased endogenous EPO was demonstrated in all sepsis models, including BiNx-CLP despite the reduced liver erythropoietin receptor (EPOR), using Western blot analysis and gene expression, in liver (partly through hepatocyte apoptosis). A high-dose EPO, but not a low-dose, attenuated sepsis in mouse models as determined by mortality and serum inflammatory cytokines. Furthermore, EPO attenuated inflammatory responses in LPS-activated macrophages as determined by supernatant cytokines and the expression of several inflammatory genes (<i>iNOS</i>, <i>IL-1</i><i>β</i>, <i>STAT3</i> and <i>NF</i><i>κ</i><i>B</i>). In parallel, patients with sepsis-AKI who were treated with the high-dose EPO showed favorable outcomes, particularly the 29-day mortality rate. In conclusion, high-dose EPO attenuated sepsis with preconditioning renal injury in mice possibly through the macrophage anti-inflammatory effect, which might be beneficial in some patients.
format	article
author	Wiwat Chancharoenthana Kanyarat Udompronpitak Yolradee Manochantr Piyawat Kantagowit Ponthakorn Kaewkanha Jiraporn Issara-Amphorn Asada Leelahavanichkul
author_facet	Wiwat Chancharoenthana Kanyarat Udompronpitak Yolradee Manochantr Piyawat Kantagowit Ponthakorn Kaewkanha Jiraporn Issara-Amphorn Asada Leelahavanichkul
author_sort	Wiwat Chancharoenthana
title	Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury
title_short	Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury
title_full	Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury
title_fullStr	Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury
title_full_unstemmed	Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury
title_sort	repurposing of high-dose erythropoietin as a potential drug attenuates sepsis in preconditioning renal injury
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/67626b2e53d945fda6d1da886504c00e
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Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury

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