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-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-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 CLPϩEPO. 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 (CLPϩEPOϩL-NAME). A fifth group (CLPϩEPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLPϩEPO rats presented significantly higher inulin clearance than did CLP and CLPϩEPOϩL-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLPϩEPO rats; and inulin clearance was significantly higher in CLPϩEPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLPϩEPO 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-␣ activation, NF-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-B downregulation.THE MORTALITY RATES OF SEPSIS and septic shock remain unacceptably high and have not changed in several decades (5,6,26,30). Acute kidney injury (AKI) occurs in ϳ50% of patients with sepsis (5, 30). In such patients, the development of AKI is predictive of a poor outcome, and the consequent mortality has been reported to be as high as 70% (5). Despite improved strategies for supporting vital organs and resuscitating patients, the incidence and mortality rates of septic AKI remain quite high (5, 6). The prevention of kidney injury in intensive care settings continues to represent a great challenge.It has been shown that NF-B mediates the transcription of a large number of genes, the products of which are known to play important roles in septic pathophysiology (24, 31). Mice deficient in those NF-B-dependent genes are resistant to the development of septic shock and to sepsis-related mortality (31). More importantly, blockade of the NF-B pathway corr...

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Por permitir que tudo isto fosse possível e por sempre me guiar na minha vocação de médica e, agora, de pesquisadora. Amém! À minha família, Aos meus pais, Maria e José, por todo o amor dedicado e por sempre priorizarem a educação dos seus filhos. Por todo o apoio, incentivo e compreensão em todas as etapas da minha vida. Aos meus irmãos Henrique José e Adriana Maria, meus grandes amigos e companheiros, por sempre me incentivarem na Medicina e compreenderem a minha ausência física em momentos importantes de nossas vidas. Obrigada por torcerem por mim de forma tão entusiasmada. Aos meus cunhados Daniela e Fernando e aos meus sobrinhos Júlia e José Henrique. O apoio e a compreensão de todos vocês foram essenciais para que eu seguisse o meu caminho. Aos meus padrinhos, Tio Romero e Tia Lourdinha, e a todos os meus tios, tias, primos e primas que sempre me apoiaram e estiveram presentes na minha vida. A torcida de todos vocês é muito importante para mim.