Abstract
Renal ischemia reperfusion (IR) is a main cause of acute kidney injury leading to high morbidity and mortality during postoperative periods. This study investigated whether ethyl pyruvate (EP) protects the kidney against renal IR injury. Male C57BL/6 mice were treated with vehicle or EP (40 mg/kg) 1 h before ischemia and the plasma creatinine (Cr) levels and tubular damage were evaluated after reperfusion. EP attenuated the IR-induced plasma Cr levels, renal inflammation and apoptotic cell death, but the effect of EP was abolished by pretreating Zinc protoporphyrin (ZnPP), a heme oxygenase (HO)-1 inhibitor. HO-1 is a stress-induced protein and protects the kidney against IR injury. EP increased significantly HO-1 expression in the proximal tubular cells in vivo and HK-2 cells in vitro. Inhibition of PI3K/Akt pathway and knockdown of Nrf2 blocked HO-1 induction by EP. High mobility group box 1 (HMGB1) secretion was assessed as an early mediator of IR injury; plasma HMGB1 were significantly elevated as early as 2 h to 24 h after reperfusion and these were attenuated by EP, but the effect of EP was abolished by ZnPP. EP also reduced HMGB1 secretion stimulated by TNF-α in HK-2 cells, and the inhibition of PI3K/Akt and knockdown of HO-1 blocked the effect of EP. Conclusively, EP inhibits the active secretion of HMGB1 from proximal tubular cells during IR injury by inducing HO-1 via activation of PI3K/Akt and Nrf2 pathway.
Highlights
Acute kidney injury (AKI) is characterized by a rapid decrease of kidney function, ranging from hours to weeks, resulting in diagnostic features of the increased blood urea nitrogen and plasma creatinine (Cr) levels
MO, USA; 40 mg/kg; intraperitoneal injection) (EP sham, n = 4); (3) mice subjected to ischemia reperfusion (IR) injury (Veh IR, n = 8); (4) mice pretreated with ethyl pyruvate (EP) 1 h prior to IR (EP IR, n = 8); (5) mice pretreated with Zinc protoporphyrin (ZnPP; Sigma; 10 mg/kg, intraperitoneal injection (i.p.)) 2 h prior to IR (ZnPP + Veh IR, n = 8), and (6) mice pretreated with ZnPP 1 h prior to EP and treated with EP 1 h prior to IR (ZnPP + EP IR, n = 8)
The results indicate that NF-E2-related factor 2 (Nrf2) activation was required for heme oxygenase (HO)-1 induction by EP in HK-2 cells
Summary
Acute kidney injury (AKI) is characterized by a rapid decrease of kidney function, ranging from hours to weeks, resulting in diagnostic features of the increased blood urea nitrogen and plasma creatinine (Cr) levels. The incidence of AKI has been reported as 2–7% in hospitalized patients and an incidence of 5–10% in intensive care unit (ICU) population and the incidence rates are steadily increasing. Despite advances in the clinical management of disease, AKI is associated with an increased risk of death in hospitalized individuals, in those admitted to the ICU with the mortality rate exceeding 50%. AKI, is associated with increased length of hospital stay and financial costs [2,3]. AKI can be induced by numerous causes which can be prerenal azotemia, intrinsic renal AKI, and postrenal AKI. Intrinsic renal AKI can be caused by tubular, glomerular, interstitial, and vascular damage. Acute tubular necrosis (ATN) is the most common cause of AKI and present in 50% of all hospital-acquired AKI [4]
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