Sharma A K, Mauer S M, Kim Y, Michael A F
Department of Pediatrics, University of Minnesota, Minneapolis, USA.
J Lab Clin Med. 1995 Jun;125(6):754-61.
We have previously characterized the evolution of renal cortical interstitial fibrosis in the rabbit model of unilateral ureteral obstruction (UUO). In our earlier report, we examined the extracellular matrix protein composition of the interstitial space. Of note, UUO was associated with the acquisition of prominent interstitial collagen IV immunoreactivity. Interstitial collagens I and III were also increased. In situ hybridization localized increased expression of collagens I and IV to cells of the interstitial space. In the current study, we examine metalloproteinase and metalloproteinase inhibitor expression in the obstructed renal cortex. Matrix metalloproteinase-2 is a metalloproteinase with activity against both collagen IV and denatured collagen I. At day 3 of UUO, both transcripts were significantly increased, although expression of these mRNAs was not different from controls after 7 and 16 days of UUO. Expression of mRNA of tissue inhibitor of the metalloproteinases (TIMP) was significantly increased in the UUO samples at all times, although it was maximal at day 3. Immunohistochemically, increased TIMP reactivity localized to the interstitial space, and TIMP mRNA expression was seen to parallel the interstitial macrophage infiltration that accompanies ureteteral obstruction. In contrast, TIMP-2 mRNA expression appeared to be biphasic, with peaks at both day 3 and day 16 of UUO. At day 7, expression was not different from controls. These data suggest a role for impaired matrix degradation in the development of interstitial fibrosis in the obstructed kidney, particularly at late times when collagen mRNA expression has returned to control values.
我们之前已描述了单侧输尿管梗阻（UUO）兔模型中肾皮质间质纤维化的演变过程。在我们早期的报告中，我们研究了间质空间的细胞外基质蛋白组成。值得注意的是，UUO与显著的间质Ⅳ型胶原免疫反应性的获得有关。间质Ⅰ型和Ⅲ型胶原也增加。原位杂交将Ⅰ型和Ⅳ型胶原表达的增加定位于间质空间的细胞。在当前研究中，我们检测了梗阻肾皮质中金属蛋白酶和金属蛋白酶抑制剂的表达。基质金属蛋白酶-2是一种对Ⅳ型胶原和变性Ⅰ型胶原均有活性的金属蛋白酶。在UUO第3天，两种转录本均显著增加，尽管在UUO 7天和16天后这些mRNA的表达与对照组无差异。金属蛋白酶组织抑制剂（TIMP）的mRNA表达在所有时间点的UUO样本中均显著增加，尽管在第3天达到最大值。免疫组织化学显示，TIMP反应性增加定位于间质空间，并且TIMP mRNA表达与输尿管梗阻伴随的间质巨噬细胞浸润平行。相反，TIMP-2 mRNA表达似乎呈双相性，在UUO第3天和第16天出现峰值。在第7天，表达与对照组无差异。这些数据表明基质降解受损在梗阻肾间质纤维化发展中起作用，尤其是在胶原mRNA表达已恢复到对照值的后期。
