肾乐和法安明防治大鼠肾小球硬化机制的探讨

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

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(matrixmetalloproteinase 9,MMP 9) /组织金属蛋白酶抑制物 1(tissueinhibitorsofmetalloproteinase 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 ,从而进一步揭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 ( 4 g·kg- 1·d- 1)及法安明 ( 10 0 0IU·kg- 1·d- 1)治疗 2 0周 ,观察大鼠血压、蛋白尿、血肌酐、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 :肾乐及法安明治疗能显著降低 5/ 6肾切除大鼠血压、蛋白尿、血肌酐、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的沉积以及下调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的表达量分别下调了 30 0 %、2 8 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 。

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 (1000IU·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 glomerulosclarosis.