The Research Of Atorvastatin’s Protective Effect And Anti-Inflammatory Mechanism On The Inflammatory Renal Injury In ARAS

Research Background：Atherosclerosis renal artery stenosis(ARAS) is one of the mainreasons leading to the end-stage renal failure. In the past, people always thought that chronicrenal insufficiency which the ARAS patients experienced was mainly due to the kidneyischemic changes caused by the renal artery stenosis. But some studies have pointed out thatthe renal parenchyma injury caused by a variety of factors may play a major role in ARASpatients’ chronic renal insufficiency progression, which may be not merely determined by therenal artery stenosis severity. Excessive oxidatie stress, renin-angiotensin system activation,lipoprotein modify product generation, capillary endothelial cell injury, renal arteryatheromatous plaques rupture, the immune response waterfalls effect caused by epithelialcells antigen attribute changes, and so on, all can cause a variety of chemotactic factors andinflammatory medium high expression, macrophages infiltration and conversion in the kidneyby activating the NF-kappa B inflammation signaling pathways, which thus leads to thedevelopment of chronic renal injury, even eventually makes the kidney develop to end-stagerenal failure.Atorvastatin is one of the most widely used statins at present. In recent years, studieshave found that statins in addition to significantly reducing of cholesterol, resistance ofatherosclerosis and cardiovascular protective effect, but also has the renal protection effectindependent of lipid-lowering, can effectively relieve the progress of chronic renal failure. Atpresent, about the study of atorvastatin in ARAS, mainly focus on the renal artery strictureand the role of atheromatous plaque progress, or the clinical contrast research betweenlipid-lowering, step-down and anticoagulation drugs combination therapy andrevascularization for patients with ARAS in the influence of renal function. whether theatorvastatin has the independent renal protective effect in ARAS patients, and the researchesof Atorvastatin’s influence mechanism on the renal injury in ARAS are pretty fewer at present. In addition to its simple lipid-lowering effect, whether atorvastatin’s anti-inflammatoryeffects also play an important role in delaying the process of chronic renal injury in ARASpatients needs further research. According to our previous studies, we find that theNF-kappaB inflammation signal pathway activation is one of the important mechanisms in theprocess of chronic renal injury leaded by ARAS. It needs to be further researched thatwhether the atorvastatin’s renal protection effect on delaying the chronic renal injury processin ARAS patients can be achieved by inhibiting the NF-kappa B inflammation signal pathwayactivation.This topic use ApoE-/-mice to establish ARAS model, through the contrast researchbetween different stages ARAS model group and its medicine group with atorvastatin, wewant to observe that if atorvastatin has the renal protection effect independent oflipid-lowering in ARAS; if the renal protection effect is caused by lipid-lowering; and ifanti-inflammatory effect of atorvastatin play an important role in delaying the process ofchronic renal damage in ARAS.While,except vivo tests,we also separate mice abdominalmacrophage and stimulate the abdominal macrophage only with LPS. At the same time wegive different concentrations intervention treatment of atorvastatin, In order to furthervalidation the anti-inflammatory effects and its mechanism of atorvastatin independent oflipid-lowering.Methods：1. In the first part, we used ApoE-/-mice to establish different stage ARAS model, and atthe same time we gave intervention treatment of atorvastatin in medicine group. Then weobserved the lipid levels, relevant index of renal injury, kidney histological change, and theactivation of NF-kappa Bp65inflammation signal pathway and macrophages in the kidney.2. In the second part, we separated the abdominal macrophage of ApoE-/-mice andstimulated the abdominal macrophage only with LPS. At the same time, we gave differentconcentrations intervention treatment of atorvastatin. Then we observed the activation ofNF-kappa Bp65inflammation signal pathway. Results:1. According to the analysis, we found the serum creatinine (Scr) and Cystatin C (Cys C)levels had no direct relation with the corresponding lipid levels in different week atorvastatintreatment groups of ARAS model. Atorvastatin had the renal protective effect independent oflipid-lowering in ARAS.2. The contrast research analysis based on ARAS model group and atorvastatin treatmentgroup of the same weeks showed that Atorvastatin could effectively delay the process ofchronic renal injury and slow down the kidney pathological histology injury aggravated.3. The contrast research analysis based on ARAS model group and atorvastatin treatmentgroup of the same weeks showed that Atorvastatin could inhibit NF-kappa B nuclearinversion of the downstream kidney in ARAS, reduce its controlled chemotactic factors,inflammatory mediator expression (such as ICAM-1, P-sel, IL-6,et al) and kidneymacrophages infiltration.4. Atorvastatin can inhibit the NF-kappaBp65nuclear inversion and downstreaminflammatory mediators IL-6mRNA expressions and IL-6secretion of ApoE-/-miceabdominal macrophage with dose dependency, which stimulated by LPS.Conclusions:1. Used ApoE-/-mice to successfully establish ARAS model, and found ARAS was agradually progressive diseases, which could lead to downstream Chronic renal damageprogress.2. Inflammation is one of the important mechanism of chronic renal damage progress inARAS, and in which the NF-kappa B inflammation signal pathway activation play a veryimportant role.3. Atorvastatin has the renal protection effect independent of lipid-lowering in ARAS,which can effectively reduce the downstream kidney inflammation of ARAS and delay theprocess of chronic renal damage. The renal protection effect of atorvastatin in ARAS may beby inhibiting the downstream kidney NF-kappa B nuclear inversion, reducing its controlledinflammatory chemotactic medium expression(such as ICAM-1, P-sel, IL-6,et al) and kidneymacrophages infiltrating to achieve.4. In vitro studies, we found that atorvastatin can inhibit the NF-kappa Bp65nuclear inversion and downstream inflammatory mediators IL-6mRNA expressions and IL-6secretion of ApoE-/-mice abdominal macrophage with dose dependency, which stimulated byLPS.