Role of collagenases and gelatinases in renal injury and their, therapeutic applications

目的：在美国和其他国家，高血压性肾硬化是导致终末期肾病的主要原因。虽然肾小球硬化的发生是由于细胞外基质成分的异常积累，但基质降解金属蛋白酶（MMPs）在肾小球损伤发病机制中的作用尚不清楚。为了研究MMP-9在高血压和肾小球硬化发病机制中的潜在作用，我们在肾小球硬化小鼠模型中研究了MMP-9缺失对血压和疾病发展的影响。方法：将MMP-9靶向缺失小鼠（MMP-9 KO）和野生型对照组分为8组，静脉注射阿霉素（20mg /kg）诱导肾小球硬化。分别于注射后4周和8周处死小鼠，分析各组小鼠尿白蛋白、血尿素氮(BUN)/肌酐水平、肾小球损伤程度和IV型胶原表达。通过测量尿液8-羟基脱氧鸟苷（8-OHdG）水平来评估氧化应激。结果：在基线时，MMP-9 KO小鼠未见高血压、蛋白尿或肾损伤迹象。阿霉素治疗在所有小鼠中引起严重的蛋白尿，但与对照组相比，MMP-9 KO小鼠的水平在4周时减弱（2.13+0.93 vs 5.71+1.40 mg/mgCr, p<0.05）。8周时，与对照组相比，MMP-9 KO小鼠pas阳性系膜基质沉积（27+3 vs 37+3, p<0.05）和IV型胶原免疫染色（36.3+4 vs 56.3+5, p<0.05）减少。所有阿霉素处理大鼠的8-OHdG水平均升高，但其水平不受MMP-9缺失的影响。不同组的血压没有变化。结论：这些结果表明，MMP-9的缺失通过一种独立于血压或氧化应激变化的机制减轻肾小球病变和蛋白尿，这与MMPs在肾小球硬化中的病理作用一致。

Objectives : Hypertensive nephrosclerosis is the leading cause of end-stage renal disease in the US and other countries. Although glomerulosclerosis occurs because of the abnormal accumulation of extracellular matrix components, the role of the matrix-degrading metalloproteinases (MMPs) in the pathogenesis of glomerular injury remains unclear. To examine potential roles of MMP-9 in the pathogenesis of hypertension and glomerulosclerosis, we examined the effects of MMP-9 deletion on blood pressure and disease development in a mouse model of glomerulosclerosis.Methods: Mice with targeted deletion of MMP-9 (MMP-9 KO) and their wild-type controls were divided into 8 groups and injected intravenously with adriamycin (20 mg/kg) to elicit glomerulosclerosis. The mice were sacrificed 4 weeks or 8 weeks after injection, and the levels of albuminuria, blood urea nitrogen(BUN)/creatinine, and degree of glomerular injury and type IV collagen expression were analyzed. Oxidative stress was estimated by the measurement of urine 8-hydroxydeoxyguanosine (8-OHdG) levels.Results : No signs of hypertension, albuminuria or renal injury were seen in the MMP-9 KO mice at baseline. Treatment with adriamycin caused severe proteinuria in all mice, but the levels were attenuated in the MMP-9 KO mice compared to controls at 4 weeks (2.13+0.93 vs 5.71+1.40 mg/mgCr, p<0.05). At 8 weeks, a decrease in PAS-positive mesangial matrix deposition (27+3 vs 37+3, p<0.05), and type IV collagen immunostaining(36.3+4 vs 56.3+5, p<0.05) was seen in the MMP-9 KO mice compared to controls. 8-OHdG levels were increased in all the adriamycin-treated rats but the levels were unaffected by MMP-9 deletion. Blood pressure was unchanged in the different groups. Conclusions : These results suggest that the absence of MMP-9 attenuates glomerular lesions and albuminuria by a mechanism independent of changes in blood pressure or oxidative stress, consistent with a pathogenetic role for MMPs in glomerulosclerosis.