Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-kappa B and upregulating endothelial nitric oxide synthase

de Souza ACCP, Volpini RA, Shimizu MH, Sanches TR, Camara NOS, Semedo P, Rodrigues CE, Seguro AC, Andrade L. Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting nuclear factor-kappa B and upregulating endothelial nitric oxide synthase. Am J Physiol Renal Physiol 302: F1045-F1054, 2012. First published January 11, 2012; doi:10.1152/ajprenal.00148.2011.-The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-kappa B activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLP + EPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-L-arginine methyl ester (L-NAME) simultaneously with EPO administration (CLP + EPO + L-NAME). A fifth group (CLP + EPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLP + EPO rats presented significantly higher inulin clearance than did CLP and CLP + EPO + L-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLP + EPO rats; and inulin clearance was significantly higher in CLP + EPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLP + EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-alpha activation, NF-kappa B activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-kappa B downregulation.

Brazilian Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, National Council for Scientific and Technological Development)

Brazilian Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, National Council for Scientific and Technological Development)

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Foundation for the Support of Research in the State of Sao Paulo)

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Foundation for the Support of Research in the State of Sao Paulo)

Laboratorios de Investigacao Medica (LIMs, Medical Investigation Laboratories) of the Faculdade de Medicina da Universidade de Sao Paulo (FMUSP, University of Sao Paulo School of Medicine) Hospital das Clinicas

Laboratorios de Investigacao Medica (LIMs, Medical Investigation Laboratories) of the Faculdade de Medicina da Universidade de Sao Paulo (FMUSP, University of Sao Paulo School of Medicine) Hospital das Clinicas

CNPq [141823/2007-0, 134318/2006-4, 309430/2006-7, 302835/2009-1]

CNPq

FAPESP

FAPESP [06/56320-0]