| Background:Renal artery stenosis with the renovascular hypertension and ischemic nephropathy which caused by the severity of stenosis as its mainly secondary pathophysiological changes, is one of the renal vascular disease caused by a variety of causes. Now the artery atherosclerosis has become the leading cause of renal artery stenosis. Therefore, the study of different types of antihypertensive drugs on the treatment of renal artery stenosis and atherosclerosis is urgent. RAS system inhibitors have a clear antihypertensive effect, and the AT1 antagonist irbesartan had been found to have the role of anti-AS, but whether the direct renin inhibitor aliskiren which also belong to inhibitors of the RAS system has the same role of anti-AS and whether its anti-AS effect is superior to irbesartan are still unkonwn. Objective:1 To establish the model of renal artery stenosis and atherosclerosis in rats;2 To compare the effects of direct renin inhibitor and AT1 antagonis on blood pressure, plasma triglycerides, total cholesterol, serum creatinine and renin activity (PRA) of rats with renal artery stenosis and atherosclerosis;3 To study and compare the effects of direct renin inhibitor and AT1 antagonis on the expression and distribution of CD68, a-SMA and MMP-1,2,9 in aortic plaque area of rats with renal artery stenosis and atherosclerosis in order to provide a theoretical basis for clinical rational and effective usage of antihypertensive drug to therapy of atherosclerosisMethods:1 establishment of the animal model:78 male SD rats were randomly divided into One Kidney One Clip(1K1C) group, Two Kidney One Clip (2K1C) group and control group. Renal artery stenosis was caused by surgery both in 1K1C group 2K1C group. Blood pressure and weight were detected both before and after the surgery,and the failure Model were eliminated. All of the rats were injected VitD350万IU/kg and feeded by high-fat for 10 weeks to establish the model of renal artery stenosis and atherosclerosis.2 After 10 weeks feeding,1K1C group and 2K1C groups were randomized intervented by drugs for 4 weeks, namely:saline group (0.9% NS2ml/d), aliskiren group (50mg/kg.d) and irbesartan group (100mg/kg.d)3 After that the following steps were given:(1) Blood collection from heart afer fasting and forbidden to drink for 8h,then detected the blood triglyceride, cholesterol, serum creatinine, plasma renin radioimmunoassay activity (PRA) by automatic biochemical analyzer; (2) taken the aorta and narrow side of the kidney in SD rats, HE staining (vascular tissue) and PAS staining (kidney) were taken in one part and the others for-70℃C cold storage; (3)using immunohistochemistry to detect the expression of CD68, a-SMA, MMP-1,2,9 in aortic arch plaque of experimental rats, comparing the average optical density values of each groups; (4) the expression of MMP2 in atherosclerotic plaques of experimental rats were detected by WB.Results:1 after the narrow method by parallel to the acupuncture needles and injection of VitD3 500000 IU/kg and high-fat diet feeding for lOweeks, the blood pressure, serum total cholesterol were increased significantly both in 1K1C and 2K1C groups compare with the control group(P<0.05),and PRA in 2K1C group were increased significantly both compare with the control and 1K1C groups(P<0.05). Plaque-like changes were found in the lumen of aortic arch by HE staining which means that renal artery stenosis and atherosclerotic rat model can be effectively established through this method.2 The effect of inhibitor of RAS system on blood pressure and other biochemical indexes of 1K1C and 2K1C groups. (1) blood pressure:both aliskiren and irbesartan can reduce blood pressure in 1K1C and 2K1C group, antihypertensive effect was more obvious in 2K1C group,but there was no significant difference in antihypertensive effect between aliskiren and irbesartan (P>0.05). (2) lipids:compare with saline group, the plasma total cholesterol was significantly reduced in 1K1C and 2K1C group by aliskiren(P<0.05), but irbesartan had no significant effect. (3) plasma creatinine:compare with the negative control group, plasma creatinine were significantly increased in1KIC and 2K1C group (P<0.05),while there was no significant difference between 1K1C and 2K1C group (P>0.05). compare with saline group, the role of RAS system inhibitors in decreasing plasma creatinine was more significant in 2K1C(P<0.05). and in which the effect of aliskiren was better than irbesartan(P<0.05). (4) renin activity:compare with the negative control group, PRA were increased both in 1K1C and 2K1C groups,in which increased significantly in 2K1C group; and PRA in irbesartan group were significantly higher than that both in saline group and aliskiren groups(P<0.05).while PRA in aliskiren group were decreased compare with saline group and irbesartan group respectively(P<0.05).3 effect of RAS system inhibitor on the formation and progress of atherosclerosis in 1K1C and 2K1C models. Compared with negative control group, a-SMA, CD68 and MMP1,2,9 were all increased in the 1K1C and 2K1C saline group (P<0.05),and compared with 1K1C group, CD68 and MMP1,2,9 increased significantly in 2K1C group(P<0.05). After the intervention of RAS system depressants,CD68, a-SMA, MMP1, 2,9 in the aliskiren group were significantly lower both than the irbesartan group and saline group(P<0.05).The results of MMP2 protein expression showed by WB were the same with immunohistochemical results.Conclusion:1 The animal model of renal artery stenosis and atherosclerosis can be effectively established by the parallel narrow method through acupuncture needles combined with fat diet and VitD3 injection, in which renin activity was significantly increased in 2K1C model, and are prone to atherosclerotic changes compared with 1K1C model.2 The effect of RAS inhibitors on antihypertensive was more significant in 2K1C model and there was no significant difference between aliskiren and irbesartan. Meanwhile both aliskiren and irbesartan can significantly reduce the the plasma creatinine in 2K1C group and this role of aliskiren was better than irbesartan.3 AT1 blocker irbesartan can play a role of anti-AS through inhibiting the macrophage CD68, a-SMA and MMP1,2,9 in plaque.4 Direct renin inhibitor aliskiren could also play a role of anti-AS through inhibit inhibiting the macrophage CD68, a-SMA and MMP1,2,9 in plaque and decreasing plasma cholesterol.this effect is stronger than the AT1 antagonist irbesartan. |
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