Tang W W, Feng L, Xia Y, Wilson C B
Department of Immunology, Scripps Research Institute, La Jolla, California 92037.
Kidney Int. 1994 Apr;45(4):1077-84. doi: 10.1038/ki.1994.144.
The accumulation of excessive extracellular matrix (ECM) following tubular injury likely represents an imbalance between ECM production and degradation. We assessed the temporal relationship between the accumulation of ECM, cell adhesion molecules, matrix degrading proteinases, and their inhibitors in a rat model of anti-tubular basement membrane (TBM) antibody-associated tubulointerstitial nephritis (TIN) by the RNase protection assay and immunohistochemistry. There was an increase in the steady state expression of fibronectin (FN) and alpha 2(IV) collagen mRNAs beginning on day 7 with the onset of neutrophil infiltration. An increase in alpha 1(III) collagen and alpha 1-integrin did not occur until days 9 and 10, respectively, at which time mononuclear leukocytes were the predominant infiltrating cell. Increased levels of FN, alpha 1(III), alpha 2(IV) and alpha 1-integrin mRNAs occurred through day 14. By immunohistochemistry, increased accumulation of collagen IV, heparan sulfate proteoglycan, and laminin were detected along the thicken TBM; collagens I and III were immunolocalized within the tubulo-interstitium, while FN was present in both the TBM and interstitium in rats with TIN on day 14. The increase in matrix accumulation was associated with little or no increase in proteinases. u-PA transcripts fell beginning on day 8, with recovery to control values by day 12. Transin mRNA was found at low levels only on days 8 and 9, and the protein could not be detected by Western blotting. In contrast, these changes were associated with an increase in proteinase inhibitors, so that TIMP and PAI-1 mRNAs increased beginning on day 7 and persisted through day 14.(ABSTRACT TRUNCATED AT 250 WORDS)
肾小管损伤后细胞外基质（ECM）过度蓄积可能代表着ECM生成与降解之间的失衡。我们通过核糖核酸酶保护试验和免疫组织化学，评估了抗肾小管基底膜（TBM）抗体相关的肾小管间质性肾炎（TIN）大鼠模型中ECM蓄积、细胞黏附分子、基质降解蛋白酶及其抑制剂之间的时间关系。从第7天中性粒细胞浸润开始，纤连蛋白（FN）和α2（IV）型胶原mRNA的稳态表达增加。α1（III）型胶原和α1整合素分别直到第9天和第10天才增加，此时单核白细胞是主要浸润细胞。直到第14天，FN、α1（III）、α2（IV）和α1整合素mRNA水平持续升高。通过免疫组织化学检测发现，增厚的TBM上IV型胶原、硫酸乙酰肝素蛋白聚糖和层粘连蛋白的蓄积增加；I型和III型胶原在肾小管间质内免疫定位，而在第14天患有TIN的大鼠中，FN存在于TBM和间质中。基质蓄积的增加与蛋白酶的少量增加或不增加相关。尿激酶型纤溶酶原激活剂（u-PA）转录本从第8天开始下降，到第12天恢复到对照值。转化生长因子β诱导蛋白（transin）mRNA仅在第8天和第9天以低水平存在，且通过蛋白质印迹法无法检测到该蛋白。相反，这些变化与蛋白酶抑制剂的增加相关，因此金属蛋白酶组织抑制剂（TIMP）和纤溶酶原激活物抑制剂-1（PAI-1）mRNA从第7天开始增加，并持续到第14天。（摘要截短至250字）
