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

Abstract

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...

Epoetin beta pegol prevents endothelial dysfunction as evaluated by flow-mediated dilation in chronic kidney disease rats

“…These results correspond to those of several previous reports showing that EPO decreased NADPH oxidase expression and activity in rat aorta (Toba et al, 2012;Wang et al, 2013). Moreover, p65 expression, which regulates transcription of NADPH oxidase, was also suppressed by C.E.R.A., corresponding to previous reports (Souza et al, 2012;Yang et al, 2011). These results indicate that C.E.R.A.…”

Progranulin protects against endotoxin-induced acute kidney injury by downregulating renal cell death and inflammatory responses in mice

“…In LPS-mediated endotoxemia, exposure of kidneys to high LPS dose leads to the production of pro-inflammatory cytokines including TNF-α and IL-6 via NF-κB signaling [36,37]. Especially, TNF-α is a pivotal pro-inflammatory mediator and IL-6 is an accessory factor [38,39].…”

Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the β-common receptor

“…20 It should be noted that the effects of EPO in sepsisinduced AKI are controversial. [32][33][34][35][36][37] Some studies report no beneficial effect of EPO in models of endotoxemia in the rat or pig. 32,33 In contrast, other studies have shown that EPO exerts beneficial effects in experimental sepsis.…”

“…Moreover, administration of EPO given 1 h after endotoxin or cecal ligation and puncture (CLP) reduces renal dysfunction and mortality in mice. 36 de Souza et al 37 recently reported their extensive investigation that pre-or post-treatment with high-dose EPO (4000 IU/kg) exhibited anti-inflammatory effects and improved survival as well as renal function in a rat model of sepsis. However, none of the above (positive) studies investigated the role of bcR in either the observed effects or the signaling events initiated by EPO.…”