肾乐和法安明防治大鼠肾小球硬化机制的探讨

目的：观察肾乐和法安明（达肝素钠）对5/6肾切除大鼠残肾组织中Ⅳ型胶原和基质金属蛋白酶-9（matrix metalloproteinase-9,MMP-9)/组织金属蛋白梅抑制物-1（tissue inhibitors of metalloproteinase-1,TIMP-1）基因表达的影响，旨在探讨两种药物对细胞外基质降解酶系MMP-9/TIMP-1的影响，从而进一步提示其减轻肾小球硬化的机制。方法：用5/6肾切除的方法诱导大鼠局灶节段性肾小球硬化模型并给予肾乐（4g·kg^-1·d^-1)及法安明（1000IU·kg^-1·d^-1）治疗20周，观察大鼠血压、蛋白尿、血肌肝、血脂和残余肾组织的病理改变程度，以及残肾组织Ⅳ型胶原、MMP-9的沉积和TIMP-1基因的表达。结果：肾乐及法安明治疗组显著降低5/6肾切除大鼠血压、蛋白尿、血肌肝、血脂和减轻肾组织的病理改变程度，并且显著减少残肾组织中Ⅳ型胶原、MMP-9沉积以及下调Ⅳ型胶原、MMP-9/TIMP-1的基因表达；定量分析结果显示，与5/6Nx组比较，肾乐组和法安明组MMP-9的表达量分析下调了30.0%、28.5%TIMP-1的表达量分别下调了59.3%、55.0%。结论：肾乐和法安明可能通过调节MMP-9/TIMP-1的基因表达，减轻肾小球重塑过程中细胞外基质的异常代谢和积聚，促进了细胞外基质的降解，这可能是肾乐和法安明防治肾小球硬化的重要作用机制之一。

Study on Mechanism of Shenle and Fragmin in Preventing and Treating Glomerulosclerosis in Rats

OBJECTIVE: To study the effects of Shenle and Fragmin on the degradation of extracellular matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinase-1 (TIMP-1) in the remnant kidneys of 5/6 nephrectomized rats treated with Shenle and Fragmin. METHODS: The model of focal and segmental glomerulosclerosis was made by 5/6 nephrectomy in Wistar rats. After being treated with Shenle (4 g.kg-1.d-1) or Fragmin (1000 IU.kg-1.d-1) for 20 weeks, the blood pressure, proteinuria, serum creatinine, lipids, renal pathological change of remnant kidney of the model animals were examined, and the mRNA expression of MMP-9, TIMP-1 and type IV collagen in the remnant kidney were also detected. RESULTS: Shenle and Fragmin could significantly reduce the blood pressure, proteinuria, serum creatinine and lipids, alleviate the pathologic change of kidney tissue, decrease the type IV collagen, MMP-9 deposition. Shenle and Fragmin down-regulated the mRNA expression of MMP-9 by 30.0% and 28.5% and TIMP-1 expression by 59.3% and 55.0% in the remnant kidney of the 5/6 nephrectomized rats respectively. CONCLUSION: Shenle and Fragmin might ameliorate glomerulosclerosis through modulating MMP-9/TIMP-1 gene expression, alleviate the abnormal metabolism and accumulation, promote extracellular matrix degradation in glomeruli remodeling, it might be the important mechanism of Shenle and Fragmin in treating glomerulosclerosis.