MMP-2、MMP-3、TIMP-1及氯沙坦与氨氯地平在老年前期自发性高血压大鼠肾硬化中的作用及其机理探讨

MMP-2,MMP-3 and TIMP-1 in glomerular sclerosis of SHR and mechanism of delaying glomerular sclerosis by treatment with losartan and amlodipine

目的 探讨MMPs/TIMPs与高血压性肾损害的关系。方法 将SHR随机分为3组,每组10只。氨氯地平10mg·kg^(-1)·d^(-1)或氯沙坦30 mg·kg^(-1)·d^(-1)治疗3个月,为实验组;以模型SHR为空白对照组。同时以10只WKY大鼠为健康对照组。测量治疗前、后血压变化,血尿素氮、肌酐和24 h尿蛋白定量,观察Ⅳ型胶原(COⅣ)、层连蛋白(LM)、基质金属蛋白酶-2(MMP-2)、基质金属蛋白酶-3(MMP-3)、基质金属蛋白酶抑制剂-1(TIMP-1)在肾组织中的表达。结果 ①SHR血压显著增高;肾功能明显受损;肾组织病理改变显著。肾小球细胞外基质(ECM)成分(如:COⅣ、LM)及TIMP-1表达增多;MMP-3、MMP-2表达减少;②治疗后,血压明显降低;肾功能损害减缓;肾组织病理改变减轻。肾组织中COⅣ、LM、TIMP-1表达减少;MMP-3、MMP-2表达增多。结论 氯沙坦与氨氯地平能延缓高血压性肾损害,改善已失调的MMPs/TIMPs比例;减少ECM在肾小球中的聚积,具有延缓高血压性肾硬化的作用。

Objective To study the role of MMP-2, MMP-3 and TIMP-1 in glomerular sclerosis of spontaneously hypertensive rats (SHR) and to study the renal protective effect of losartan and amlodipine on SHR. Methods After the treatment with losartan(30 mg/kg·d)and amlodipine(10 mg/kg·d)for 3 months, the blood pressure (BP), urine protein (UP), the renal pathological lesions, and the expression of collagen Ⅳ (CoⅣ), laminin (LM), matrix metalloproteinase (MMP)-2, MMP-3 and tissue inhibitor of metalloproteinase (TMP)-l in the SHR and Wistar-Kyoto(WKY)rate (control) were studied. Results Losartan and amlodipine not only reduced BP, 24h UP and renal injuries, but also significantly decreased the expression of CoⅣ and LM, modulated MMPs/TIMPs and ameliorated glomerular sclerosis in SHR. Conclusions The modulating effect of losartan and amlodipine on the ratio between MMPs and TIMPs and on the extracellular matrix (ECM) metabolism through the direct and indirect pathways may be one of the therapeutic mechanisms of ATRA and CCB in ameliorating glomerular sclerosis.