Effects of continuous erythropoietin receptor activator in sepsis-induced acute kidney injury and multi-organ dysfunction

Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remai...

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Published in:	PloS one Vol. 7; no. 1; p. e29893
Main Authors:	Rodrigues, Camila E, Sanches, Talita R, Volpini, Rildo A, Shimizu, Maria H M, Kuriki, Patrícia S, Camara, Niels O S, Seguro, Antonio C, Andrade, Lúcia
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 03-01-2012 Public Library of Science (PLoS)
Subjects:	Acute Kidney Injury - etiology Acute Kidney Injury - prevention & control Analysis Animals Aquaporin 2 Aquaporins Biological response modifiers Biology Body weight Cecum Cecum - surgery Creatinine Cytokines Cytokines - metabolism Erythropoietin Erythropoietin - pharmacology Gene Expression Regulation - drug effects Health aspects Hemodynamics - drug effects Immunoblotting Immunohistochemistry Infection Infiltration Inflammation Inflammatory response Interferon Interferon gamma Interleukin Interleukin 10 Interleukin 6 Interleukins Ischemia Kidney Tubules - drug effects Kidney Tubules - metabolism Kidneys Kinases L-Lactate dehydrogenase Lactate dehydrogenase Lactic acid Ligation - adverse effects Macrophages Macrophages - drug effects Macrophages - immunology Male Medicine Metastases Mortality Multiple Organ Failure - etiology Multiple Organ Failure - prevention & control NF-kappa B - metabolism NF-κB protein Organs Pharmacology Plasma levels Polyethylene Glycols - pharmacology Pretreatment Punctures - adverse effects Rats Rats, Wistar Receptors, Erythropoietin - metabolism Rodents Sepsis Sepsis - complications Sepsis - etiology Sepsis - immunology Sepsis - metabolism TLR4 protein Toll-Like Receptor 4 - metabolism Toll-like receptors Transaminases Tumor necrosis factor-TNF Tumor necrosis factor-α Brazil United States > US
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Summary:	Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI. RATS WERE RANDOMIZED INTO THREE GROUPS: control; CLP; and CLP+CERA (5 µg/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting--to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-κB)--and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1β, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection. Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-κB was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats. CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Performed the experiments: CER TRS RAV MHMS PSK. Analyzed the data: CER NOSC ACS LA. Contributed reagents/materials/analysis tools: CER TRS RAV MHMS PSK NOSC ACS LA. Wrote the paper: CER LA.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0029893