Erythropoietin treatment improves liver regeneration in a rat model of living related liver transplantation via upregulation of c-jun and inhibition of apoptosis

Introduction: Inadequate liver regeneration is still an unsolved problem in the setting of living donor liver transplantation (LDLT). Therefore, we have investigated the use of erythropoietin (EPO) as an exogenous stimulator of liver regeneration in a rat model of LDLT.

Materials and Methods: Male Lewis rats were treated before operation and perioperatively with EPO or heat-inactivated EPO-vehicles, respectively. Animals underwent a 30% partial liver transplantation (pLTx). Serum and liver samples were taken to investigate liver function, liver body weight ratio (LBWR), hepatocyte proliferation (Ki–67), apoptosis markers (TUNEL assay), IL–6/TNF-α (ELISA) and angiogenesis (vessel area and perimeter). 24h after pLTx the expression of 183 genes involved in liver regeneration and apoptosis were measured by means of an in-house cDNA array (confirmation of the results by quantitative RT-PCR). Additionally, the overall survival was assessed.

Results: Exogenous administration of EPO led to improved liver regeneration as shown by an increased LBWR. There also was a tendency towards an improved postoperative coagulation. 24h after pLTx EPO treatment clearly induced an upregulation of the immediate-early gene c-jun (2,89±0,62 vs. 1,51±1,07; p<0.05) and increased the expression of the antiapoptotic marker bcl-Xl, which was associated with a significantly lower proportion of hepatocytes undergoing apoptosis. No differences could be found concerning IL–6/TNF-α and angiogenesis. In addition, EPO-treated rats showed a significantly improved survival.

Discussion: EPO treatment clearly improved liver regeneration and survival in a rat model of LDLT. The underlying mechanisms seem to include an increased expression of the well-known liver regeneration-mediator c-jun as well as the downregulation of apoptotic pathways. Exogenous administration of EPO may therefore represent a promising strategy to optimize extended liver resections and especially LDLT in the future.

erythropoietin - liver regeneration - living related liver transplantation