Inhibition of matrix metalloproteinases during chronic allograft nephropathy in rats
Inhibition of matrix metalloproteinases during chronic allograft nephropathy in rats
复制标题
DOI：
10.1097/01.tp.0000151644.85832.b5
复制
发表时间：
2005-03-27
期刊：
影响因子：
6.2
通讯作者：
Heemann, U
中科院分区：
文献类型：
--
作者：
Lutz, J;Yao, YS;Heemann, U
背景资料。慢性移植物肾病(CAN)是导致长期移植肾功能衰竭的主要原因。组织学特征之一是间质纤维化，受到控制细胞外基质(ECM)降解的基质金属蛋白酶(MMPs)的影响。到目前为止，MMPs是否影响CAN的发生发展尚不清楚。为了分析MMPs在CAN中的作用，我们在大鼠肾移植模型上观察了早期和晚期应用BAY 12-9566(一种基质金属蛋白酶-2、-3和-9的抑制剂)对CAN发生和发展的影响。分别于移植后前10天(早期治疗)或移植后12周~20周(晚期治疗)用Bay12-9566(15 mg/kg/d)或赋形剂(15 mg/kg/d)治疗的Lewis受者行Fisher肾原位移植。每4周分析一次蛋白尿，直到移植后20周摘除移植肾进行进一步分析。早期抑制基质金属蛋白酶导致24小时蛋白排泄量显著减少，与20周后较低级别的CaN平行。然而，与对照组相比，移植后12周开始晚期抑制MMP导致显著增加的蛋白尿和更高级别的CaN。此外，转化生长因子-β和血小板衍生生长因子-B链的mRNA水平在这些动物中显著升高。移植后早期抑制MMPs减少了CAN的发生和进展，但如果在后期启动则促进了CAN的发生和发展。因此，MMI参与了CAN的发展和进展。
Background. Chronic allograft nephropathy (CAN) belongs to the major causes of long-term kidney allograft failure. One of the histologic hallmarks of CAN is interstitial fibrosis, influenced by matrix metalloproteinases (MMPs) that are controlling extracellular matrix (ECM) degradation. Whether MMPs affect the development and progression of CAN is not clear so far. To analyze the role of MMps in CAN, we investigated the effects of an early and a late application of BAY 12-9566, an inhibitor of MMP-2, -3, and -9 on the development and progression of CAN in a rat kidneytransplantation model.Methods. Fisher kidneys were orthotopically transplanted into Lewis recipients that were treated with BAY 12-9566 (15 mg/kg per day) or vehicle either for the first 10 days after transplantation (early treatment) or from week 12 to week 20 after transplantation (late treatment). Proteinuria was analyzed every 4 weeks up to week 20 after transplantation when kidney grafts were removed for further analysis.Results. Early MMP-inhibition resulted in a significantly reduced 24-hour protein excretion that was paralleled by a lower grade of CAN after 20 weeks. However, late MMP inhibition starting at week 12 after transplantation resulted in significantly higher proteinuria and a higher grade of CAN as compared with controls. Furthermore, transforming growth factor-beta and platelet- derived growth factor-B chain mRNA levels were significantly increased in these animals.Conclusions. Inhibition of MMPs early after transplantation reduced the development and progression of CAN but promoted CAN if initiated at later stages. Thus, MMI's are involved in the development and progression of CAN.