Nephroprotection through the Akt/eNOS pathway by centrally administered erythropoietin in a rat model of fixed-volume hemorrhage

This study was designed to investigate the protective effects of centrally administered erythropoietin (EPO) on brain oxidative stress and inflammatory markers to protect the kidneys during hemorrhagic shock (HS). Animals were assigned into three groups (n=6). Sham rats were subjected to cannulation of femoral artery and vein as well as stereotaxic surgery. In HS group, 50% of total blood volume was withdrawn and resuscitation was started 2h later. In EPO group, stereotaxic surgery in lateral ventricle was performed one week before induction of HS for administration of EPO (2IU) just before resuscitation. Plasma samples, kidney and brain tissues were allocated after a further 3h in all animals. There was a significant increase in survival rate in the EPO group (69.3%) compared to the HS group (35.7%). Brain EPO administration significantly attenuated the rises in BUN, plasma Cr and NGAL, brain and renal MDA content and also increased SOD activity in the kidney and brain compared to the HS group. Brain, plasma and kidney TNF-α and IL-6 levels were significantly reduced by EPO compared to HS group. EPO increased the phosphorylation of Akt on Ser473 and eNOS mRNA expression in the kidney tissue compared to the HS group. In conclusion, centrally administered EPO reduced pro-inflammatory and oxidative stress indices in the kidney and reduced apoptosis by activation of the Akt/eNOS signaling pathway. Hence, it can be hypothesized that EPO may play a major role in the central regulation of renal system as a neuromodulator.