| Acute kidney injury(AKI)is a group syndrome characterized by rapid decline in kidney function.AKI can develop into acute renal failure,in which the main pathophysiological change is ischemia hypoxia with extensive and complex and oxidative stress reaction,leading to renal tubular epithelial cell dead necrosis.AKI caused by ischemia/reperfusion injury(I/R)is one of the most common clinical events,in cardiovascular surgery,trauma and renal transplantation with an incidence rate of 3-5%.The existing renal support or replacement therapy can not promote kidney regeneration or repair of kidney damage.Thus,some patients still developed chronic kidney injury in different degree because of renal tubular epithelial cell structure and function destruction.Therefore,it is important to explore the strategies to promote renal regeneration and repair of renal tubular epithelial cells to improve the prognosis of ischemic AKI.Ischemia reperfusion injury refers to the phenomenon that cellular function of metabolism and structural damage get worse when tissues or organs restored blood flow after a period of ischemia.Renal ischemia reperfusion injury is a commonclinical pathological and physiological phenomenon,with a complex pathological process involving many factors including ATP reduceiton,generation of oxygen free radicals,cell calcium overload,overexpression of inflammatory mediators and adhesion molecules,excessive nitric oxide synthesis and other factors.Oxidative stress is an important approach,which has been proved to be help the pathogenesis of renal ischemia-reperfusion injury.Moreover,oxidative stress induced by renal ischemia reperfusion injury also produces high levels of reactive oxygen species(ROS).Excessive ROS leads to lipid peroxidation,DNA mutation,apoptosis and necrosis,resulting in various ways of cell death.These evidences suggest that oxidative stress can promote renal ischemia-reperfusion injury.Nuclear factor E2(nuclear factor-E2)correlation factor 2(related factor2)referred to as "Nrf2,cellular defense mechanism against oxidative stress is one of the more important step.Nrf2 is located in the nuclei of antioxidant and detoxification gene promoter regions,is very sensitive to oxidative stress for a gene transcription factor,when oxidative stress,Nrf2 can with their partners in the cytoplasm keap1 dissociation,phosphorylation into the nucleus and regulate various antioxidant enzymes are related to start.Nrf2 signaling pathways that regulate HO-1 is the speed limit enzyme of heme degradation,widely distributed in the tissues,mainly in the smooth endoplasmic reticulum.So far have found that there are three kinds of HOisozyme,HO-l respectively,2 and HO,HO,a 3,HO-1 is important cell protection factor,antioxidant,anti-inflammatory and anti apoptosis,and other functions.Statin is a a natural compound.By inhibiting specifically to HMG-CoA from converting to Mevalonate,thereby blocking the synthesis of cholesterol,lowering blood cholesterol levels.Statins have been widely used in clinical treatment of hyperlipidemia.In recent years,it has been found that statins still have a strong non lipid-lowering effect.This non lipid-lowering effect is also considered the pleiotropic effects of statins,which mainly include: improving degree and improve endothelial function,oxidative stress,inflammation,inhibition of extracellular matrix accumulation and decreased vascular smooth muscle cell migration and proliferation and immune regulation by nitric oxide biology.As reported in animal experiments,statin could effectively improve the kidney internal ischemia reperfusion injury caused by oxidative stress and inflammatory reactionThe aim of this study was to investigate the effects of statin on renal ischemia reperfusion injury and to provide the molecular basis for the treatment of renal injury,based on the meta analysis of statin on ischemia reperfusion injury.Part one: meta analysis of the protective effects of statins on human organs’ ischemia reperfusion injuryIn this part,meta analysis was used to study the protective effect of statins on the ischemia reperfusion injury of human organs.We use NCBI PubMed database,select the time since the establishment of the database to 2017.The keyword was set as“statin AND ischemia reperfusion injury”.Inappropriate articles were delete.The data of patient grouping,gender,age,medication treatment,and the number of patients with ischemic reperfusion injury were extracted.Finally,we use RevMan5.3.5software to analyze and evaluate all the extracted data by meta.The results of meta analysis showed that the incidence of ischemia reperfusion injury was increased(OR:0.07,95%CI:0.12,P<0.00001).Meta results showed that,compared with the control group,the use of statins before and after the occurrence of ischemia reperfusion injury in reducing the severity of ischemia reperfusion injury has a significant advantage.The use of meta analysis does not distinguish between the statin in ischemia reperfusion before and after,but the results strongly support the use of statins in ischemia reperfusion early prevention and after treatment,to reduce ischemia and further damage to organ perfusion.Part two: the protective effect of statin pretreatment in rats with renal ischemia reperfusion injuryThis part of the experiment was designed to study the protective effects of statin on SD rat renal ischemia reperfusion injury model.After the establishment of rat renalischemia reperfusion model,evaluation of renal function changes in different groups and renal tissue for histological examination and TUNNEL staining to observe the change of necrosis and apoptosis.Then expression and transcription of certain protein was detected.In this study,it was found that renal ischemia reperfusion injury resulted in a significant reduction in renal function,leading to necrosis and apoptosis in renal tissue,especially in renal proximal tubular epithelial cells.statin can effectively relieve renal damage,tissue injury and apoptosis induced by renal ischemia reperfusion.Moreover,the therapeutic effect is related to two proteins Nrf-2 and HO-1.Part three: the protective effect and mechianism study of statin pretreatment on renal proximal tubular epithelial cell lines HK-2The part was designed to study the main pathogenesis of acute renal injury.By comparing the cell growth inhibition rate,MDA and SOD levels at different concentrations of CoCl2 and different hypoxia time,the optimal anoxic conditions in the follow-up study were determined.To determine the optimum conditions of hypoxia treatment,different reatment was applied to detect the inhibition rate of cell growth,the difference between MDA and SOD levels,apoptosis level and related protein expression including Keap1,Nrf2,Ho-1,and p38 to study mechanism ofstatin pretreatment protecting ischemia reperfusion injury in renal proximal tubular epithelial cells.The results in this part proves that statin has a significant therapeutic effect in human renal tubular epithelial cell line HK-2 hypoxia model.The growth of cells in hypoxia after statin treatment group was significantly better tha in hypoxia group,with lower MDA and higher SOD value than that of hypoxia group.statin significantly inhibited hypoxia induced apoptosis.And the therapeutic effect is achieved through the P38-Nrf2/Keap-HO-1 signaling pathway.In summary,statin through Nrf2/Keap-HO-1 pathway inhibits ischemia reperfusion resulted oxidative stress in renal tubular epithelial cells,decreasing the necrosis and apoptosis.This biological activity against ischemia reperfusion injury might provide new ideas for clinical treatment of ischemia reperfusion injury. |
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