Renoprotective effect of erythropoietin via modulation of the STAT6/MAPK/NF-κB pathway in ischemia/reperfusion injury after renal transplantation

Abstract

Ischemia/reperfusion injury (IRI) commonly occurs in renal transplantation. Erythropoietin (EPO) exerts a protective effect in IRI. To investigate the underlying molecular mechanism, rat models of renal IRI were established and treated with EPO and/or lentivirus-mediated EPO-siRNA , the signal transducer and activator of transcription 6 (STAT 6) inhibitor AS1517499, the JN K inhibitor SP600125, the p38 mitogen-activated protein kinase (MA PK) inhibitor SB203580, and the nuclear factor (NF )-κB inhibitor lactacystin. Histological examination revealed that EPO protected the kidney from IRI , through decreasing the extent of tissue congestion and inflammatory cell infiltration; however, EPOsiRNA did not exert the same protective effect. In addition, the EPO level was inversely associated with renal IRI . EPO downregulated the expression of interferon-γ, interleukin (IL)-4, creatinine and caspase-3, and upregulated the expression of IL -10, thymic stromal lymphopoietin, STAT 6, p-JN K and p-p38, while the opposite effects were observed with the administration of EPO-siRNA and the specific respective inhibitors. Further results revealed that MA PK (p-JN K and p-p38) acted upstream of NF -κB, and that NF -κB signaling regulated the expression of caspase-1 and -3, which may be responsible for the cytotoxicity associated with IRI . Taken together, the results of the present study demonstrated that EPO exerted a protective effect in renal IRI via the STAT 6/MA PK/NF -κB pathway. This protective effect of EPO may improve reperfusion tolerance in ischemic kidneys and benefit transplant recipients.