Expression Of AGEs-RAGE In The Brain Tissue Of The Spontaneously Hypertensive Rat And The Interventional Effect Of Drug

Background:Today hypertension has become a commonly and frequently encountered disease.The impairment of the cerebral vessel is one of the most important complication of hypertension.It is well known to all that persistent hypertension causes pathological change of systemic anteriola,which is represented by the hyperplasy and fibrosis of vessel intermedial smooth muscles,the thickening vessel wall,and stenosis of lumens. The eventual results of the above mentioned pathogenesis are brain atrophy and functional deterioration.Oxidative stress is important in the pathogenesis of hypertension complication. High level active oxygen(ROS)can affect the activity and expression of antioxidases which can clear free radicals in hypertension.There is evidence that hytertensive stimuli,such as high salt and angiotensionⅡ,promote the production of ROS contributes either to hypertension or to the complication of hypertension.Advanced glycation end products (AGEs) develop through complex, sequential reactions, collectively called the Maillard reaction. Accumulation of AGEs in tissues has been implicated in the progression of chronic diseases, these compounds have also been shown to play a pivotal role in acute and chronic atherosclerotic disease, causing structural protein changes in the vascular wall, as well as activating cellular receptors, such as the receptor for AGEs(RAGE),which in turn leads to activation of several oxidative and inflammatory pathways .Hypertension is one of atherosclerotic disease.AGEs and its receptors (RAGE) also play an important role in pathological terms of hypertension complication. Engagement of RAGE by AGEs activates its downstream signaling and subsequently evokes oxidative stress and inflammatory responses,thus contributing to the development and progression of hypertension. Therefore,inhibition of the AGEs-RAGE expression may be a promising target for therapeutic intervention in this devastating disorder.Objective:1.To explor the condition of oxidative stress in the brain tissue of SHR.2.To observe the expression of AGEs-RAGE system (CML,RAGE,NF-κB,VCAM-1,ICAM-1)in the brain tissue of the SHR model rats.3. To investigate changs of AGEs-RAGE system, oxidative stress in brain tissues of SHR model rat interferd with Telmisartan and Pridoxamine4.To research the effect and role of AGEs-RAGE system, oxidative stress on brain damage caused by hypertension, and to explore the possible effective treatment of it in the early stage.Methods:48 SHR male rats with 24 weeks'ages were divided averagely into four groups at random:the spontaneously hypertensive rat group(HC group, lavaged with water 2ml), the Telmisartan treatment group(T group lavaged with Telmisartan 8mg/kg),the Pridoxamine treatment group(P group lavaged with Pridoxamine 200mg/kg), the Telmisartan and Pridoxamine treatment group(TP group lavaged with Telmisartan 8mg/kg and Pridoxamine 200mg/kg). The homongenous WKY rats were 12 Wistar-kyoto rats,served as the normal control group(NC group, lavaged with water 2ml).All the rats had been fed for 16 weeks.At the end of the 16th week ,the weight and blood pressure were valued.Activities of superoxide dismutase(SOD),maleic dialdehyde (MDA)were measured by chromatometry.The expression of RAGE,NF-κB were detected by Quantitative real-time PCR.The expression of RAGE was detected by immunohistochemistry. Western Blot was performed to detect the expression of CML,RAGE,NF-κB,VCAM-1,ICAM-I.Rusults:1.Effect of Telmisartan and Pridoxamine on the Blood Pressure of SHRThe blood pressure was obviously higher in the HC,T,TP group than that in NC group(P<0.01);after drug interference for 16 weeks,the T group and TP group was obviously reduced compared with HC group(P<0.01).There were no obvious difference between P group and HC group(P>0.05).2.The Pathological changes of hippocamps in groupsHE staining displayed that the pyramidal neuron of the hippocamp CAI in NC group had regulated shape and quantity with clear caryotheca, conspicuous nucleolus and lined up in order;However,the pyramidal neuron of the hippocamp CA1 in HC group had unregulated shape and the less quantity with loose matris and pyknosis.The shape and quantity of the pyramidal neuron of the hippocamp CAI in T group,P group and TP group were between NC groups and HC group, pyknosis were less than it in HC group.3.The activities of SOD and the level of MDACompared with NC group,the level of MDA in HC group significantly increased,the activities of SOD in HC group significantly decreased (P<0.05);Compared with HC group,the level of MDA in T group,P group and TP group significantly decreased,the activities of SOD in T group,P group and TP group significantly increased (P<0.05).4. ImmunohistochemistryThe expression of RAGE was mainly on the cellular membrane and kytoplasm of the pyramidal neuron of the hippoeamp CAI in NC group,the expression was fairly Poor;The expression of RAGE in the hippocamp CA1 was strongly positive;Compared with HC group,the expression of RAGE significantly decreased,the quantity of positive cell decreased.5.Consequence Western blotting (1)Compared with NC group, the expression of CML significantly increased in HC group (P<0.01),Compared with HC group,the level of CML in T group,P group and TP group significantly decreased (P <0.01);(2)Compared with NC group, the expression of RAGE in HC group significantly increased (P<0.01),Compared with HC group,the level of RAGE in T group and TP group significantly decreased (P<0.01). There were no obvious difference between P group and HC group(P>0.05).(3) Compared with NC group, the expression of VCAM-1,ICAM-1 significantly increased in HC group (P<0.01),Compared with HC group,the level of VCAM-1,ICAM-1 in T group,P group and TP group significantly decreased (P<0.01).6.The mRNA expression of RAGE,NF-κBThe mRNA expression of RAGE,NF-κB in HC group was significantly higher compared to those in NC group(P<0.01);Compared with HC group,the mRNA expression of NF-κB significantly desceased in T group,P group and TP group;the mRNA expression of RAGE was no significantly difference between P group and HC group.Conclusion:1.Hypertension can up-regulate the expression of ROS and decrease the activity of antioxidase in brain,it is hypothesized that increased the level of oxidative stress might lead to the brain damage of hypertension.2.Hypertension can up-regulate the expression of AGEs-RAGE,activate NF-κB and VCAM-1,ICAM-1.3. Telmisartan and Pridoxamine may inhibit the expression RAS and AGEs-RAGE, decrease oxidative stress ,delay progression of brain damage in hypertension.4. AGEs-RAGE might play a part in the harm of the brain caused by hypertension.5. Telmisartan and Pridoxamine might prevent brain harm caused by hypertension the early stage.