Effect Of EPO On Endoplasmic Reticulum Stress In Rats Model Of Acute Kidney Injury With Ischemia-Perfusion

Background:Acute renal failure is equal with acute renal tubular injury, which has high mortality. Untill now, the therapy for ARF is mainly with only support or replacement therapy. Erythropoietin(EPO) promote erythroid cell’s survival, proliferation and differentiation by binding the EPO receptor(EPOR) on the cell surface. In recent years, researchers found that EPOR not only on erythroid cell but also on nerve cells, heart cells and tubular epithelial cells. It has been demonstrated that EPO has therapeutic effect on both cerebral ischemia and myocardial infarction. Now, the study of EPO in AKI with ischemia-reperfusion has also been increasing. It is suggested that renal protection mechanism of EPO might relate to activation of the downstream proapoptotic procesure of JAK2signal pathway. Endoplasmic reticulum stress(ERS) is commonly respond to stress in subcellular level. ERS induce unfolded protein response(UPR), then activate PERK, ATF6and IRE1pathway. UPR has double faces that protects cell in early stage and have a proapoptotic role by activating CHOP, JNK and Caspase12death pathway.Objectives:This study was to examine whether the beneficial effect of erythropoietin on ischemia-reperfusion induced acute kidney injury was related to the inhibition of ERS-UPR pathway.Methods:One hundred and four300-350g male SDrats were randomly assigned into4experimental groups as Sham+NS(n=20), Sham+EPO(n=20), IR+NS(n=32) and IR+EPO(n=32), and4ischemia-reperfusion period groups as1hr,3hr,6hr and24hr. There was5rats in the sham groups each and8in the ischemia-reperfusion groups each ischemia-reperfusion period. A single dose of5000IU/kg EPO or the same volume NS, according to the groups, were injected intraperitoneally2hrs prior to occlusion. For the ischemia-reperfusion group, bilateral kidneys underwent90min ischemia by clamping renal pedicles. Animals were sacrificed at1,3,6and24hrs after reperfusion to obtain kidney and venous blood samples.The serum concentration of Cr and BUN were measured. Proapoptotic effect was evaluated according to semi-quantitive analysis of CHOP levels by immunohisto-chemistry method. The serum concentration of MCP-1, IL-1β, IL-6and TNF-a were measured by ELISA.Results:(1) SCr and BUN level in the IR+NS group increased significantly at1h after reperfusion compared with Sham+NS group (P<0.001),and became higher as ischemia-reperfusion period prolonged.(2) At four time points (1hr,3hr,6hr and24hr)of ischemia-reperfusion groups with EPO administration, the values of SCr, BUN, CHOP and cytokines including MCP-1,IL-1β,IL-6and TNF-a were lower than NS control groups. The values of SCr and CHOP in3and24hours IR+EPO groups and the values of BUN, MCP-1, IL-1β,IL-6in24hours IR+EPO groups had significant difference(P<0.05) compared with IR+NS groups.(3)In1hour groups, ischemia-reperfusion groups had no significant difference compared with sham groups. In3,6and24hours groups, IR+NS groups had significant difference compared with sham+NS groups(P<0.05).Conclusion:(1)Ischemia-reperfusion insult may caused significant acute renal injury.(2) EPO treatment reduced the serum SCr, BUN, MCP-1,IL-1β, IL-6and TNF-αlevels in the schemia-reperfusion rats.(3)Acute ischemia-reperfusion could induce ERS, and EPO downregulated the level of CHOP expression. The renal protection of EPO is probably related to inhibition of ERS-UPR pathway. It needs to be studied further.