Evaluation of The Renoprotective Effect of Erythropoietin Against Acute Kidney Injury (AKI) Through Alleviation of Oxidative Stress, Innate Immune Response and Inflammation

Acute kidney injury (AKI) is a prevalent and complex pathological problem mainly consequences from heterogeneous mechanisms. AKI can emerge from a diversity of triggers, like ischemia reperfusion (IR) injury, experience to nephrotoxic agents, and sepsis. Ischemia-RI is among the most frequent reasons for AKI. AKI presents as a serious global public health concern effecting around 13.3 million patients each year, which is escorted by high morbidity, mortality (1.7 million associated deaths), and healthcare costs. This clinical syndrome occurs in (2-5) percent of hospitalized patients and about 50 percent in intensive care unit setting. Persons who suffer AKI in numerous settings are at greater risk of cardio-vascular problems, chronic and/or end stage renal illness, and death. Erythropoietin (EPO) is considered as a hematopoietic glycoprotein hormone synthesized mainly via the adult kidneys and mainly used in management of the anemia. Far away from its erythropoietic impacts, EPO also displays cytoprotective effects contra IRI in various tissues including renal, cardiac, hepatic in addition to central nervous system. Throughout the ischemic period, EPO receptor will be increased. The object of the current work was to explore the renoprotective mechanisms of the erythropoietin in IR induce AKI. Eighteen rats were randomly distributed into three groups (No. 6 each group) with and without IRI. The Sham group was rats underwent all operation procedures in the absence of ischemia and reperfusion. The control group (6 rats) were exposed to IR and pretreated with distil water (as a vehicle of erythropoietin) one hour ago. Erythropoietin group (6 rats) as in control group but pretreated with erythropoietin (1000 U/kg). Serum urea and creatinine in addition to histopathological tests were used to evaluate the effect of erythropoietin on renal function. Antiinflammatory and antioxidant effects were investigated by measuring IL-1β and F2-Isoprostan levels in kidney tissue. Suppressing impact of erythropoietin on innate immune system was assessed by measuring both HMGB-1 level by ELIZA and TLR4 protein expression by immunohistochemical technique. Erythropoietin displayed renoprotective effect through reducing the levels of serum urea and creatinine in addition to amelioration of histological change comparing to control group. The result also showed antiinflammatory andantioxidant effects by reducing IL-1β and F2-Isoprostan levels that are elevated during IR. HMGB-1 and TLR4 showed elevated in control group but erythropoietin pretreated led to decreased these innate immune markers. The data here identify three therapeutic effects that could be utilize in clinical study. The first one is the erythropoietin, which exhibited remarkable efficacy alleviating renal inflammation through IRI. The second is the erythropoietin inhibits innate immune response through blocking HMGB-1/TLR4 signaling pathway. The third is erythropoietin effect in renal IRI may be further pleiotropic due to of its mode of action agonist oxidative stress.