Keeton M, Ahn C, Eguchi Y, Burlingame R, Loskutoff D J
Department of Vascular Biology, Scripps Research Institute, La Jolla, California, USA.
Kidney Int. 1995 Jan;47(1):148-57. doi: 10.1038/ki.1995.17.
Many renal diseases are associated with fibrin deposition in the glomeruli, a situation that reflects an abnormality in the balance between the coagulation and fibrinolytic systems. We recently demonstrated that normal mouse kidney contains very low levels of type 1 plasminogen activator inhibitor (PAI-1), a potent anti-fibrinolytic protein, but that during endotoxemia, large amounts of PAI-1 protein and mRNA are expressed in glomerular and peritubular endothelial cells. These results raise the possibility that overexpression of PAI-1 in the glomerulus may contribute to the ongoing pathology seen in renal disease. To directly investigate this possibility, we studied PAI-1 expression in MRL/lpr mice, using in situ hybridization and immunohistochemistry. Female MRL/lpr mice develop early onset lupus glomerulonephritis (GN), a disease in which fibrin deposition is detected in the glomerulus and in which anti-coagulation therapy improves the prognosis. We detected very low levels of PAI-1 mRNA and antigen in the smooth muscle cells of renal vessels and in the renal papilla of 16 control mice. In contrast, PAI-1 was expressed in relatively high levels throughout the kidneys of 33 out of 34 diseased mice, both within the glomerulus and also in tubules and vessels. Moreover, the level of PAI-1 in the tissues seemed to correlate with the severity of the disease. PAI-1 expression was localized to endothelial cells, parietal epithelial cells, tubular epithelial cells and infiltrating mononuclear cells in the tubulointerstitium. None of these cells express detectable levels of PAI-1 in the normal kidney. The inappropriate expression of PAI-1 in the kidneys of mice with lupus GN suggests that this important inhibitor of fibrinolysis may play a role in the pathogenesis of this disease process.
许多肾脏疾病都与肾小球内纤维蛋白沉积有关，这种情况反映了凝血和纤溶系统之间平衡的异常。我们最近发现，正常小鼠肾脏中1型纤溶酶原激活物抑制剂（PAI - 1）的含量极低，PAI - 1是一种强效抗纤溶蛋白，但在内毒素血症期间，肾小球和肾小管周围内皮细胞中会大量表达PAI - 1蛋白和mRNA。这些结果提示，肾小球中PAI - 1的过度表达可能导致了肾脏疾病中持续存在的病理变化。为了直接探究这种可能性，我们利用原位杂交和免疫组化技术研究了MRL/lpr小鼠中PAI - 1的表达情况。雌性MRL/lpr小鼠会早期发病，患上狼疮性肾小球肾炎（GN），这种疾病在肾小球中可检测到纤维蛋白沉积，抗凝治疗可改善其预后。我们在16只对照小鼠的肾血管平滑肌细胞和肾乳头中检测到极低水平的PAI - 1 mRNA和抗原。相比之下，在34只患病小鼠中，有33只小鼠的整个肾脏中PAI - 1表达水平相对较高，在肾小球以及肾小管和血管中均有表达。此外，组织中PAI - 1的水平似乎与疾病的严重程度相关。PAI - 1表达定位于内皮细胞、壁层上皮细胞、肾小管上皮细胞以及肾小管间质中的浸润单核细胞。在正常肾脏中，这些细胞均未表达可检测水平的PAI - 1。狼疮性GN小鼠肾脏中PAI - 1的不适当表达表明，这种重要的纤溶抑制剂可能在该疾病进程的发病机制中发挥作用。
