DIFFERENT EXPRESSION OF THE PLASMINOGEN ACTIVATION SYSTEM IN RENAL THROMBOTIC MICROANGIOPATHY AND THE NORMAL HUMAN KIDNEY

Renal thrombotic microangiopathy is characterized by glomerular and va scular thrombosis. The persistancy of fibrin deposits may result from imbalance between plasminogen activation and inhibition. In the presen t study, we used immunohistochemistry and in situ hybridization techni ques to determine the localization of urokinase-type (u-PA) and tissue -type (t-PA) plasminogen activators, type 1 plasminogen activator inhi bitor (PAI-1) and membrane receptor for u-PA: (uPA-R) antigen and thei r sites of synthesis in renal thrombotic microangiopathy (N=10) as com pared to acute tubular necrosis (N=5) and normal human kidneys (N=7). We found an induction of PAI-1 and uPA-R expression in glomeruli and i n arterial walls in renal thrombotic microangiopathy. In addition, the induction of uPA-R expression was also found in some tubular epitheli al cells. In most cases, local synthesis of PAI-I and u-PA-R was confi rmed by in situ hybridization with the corresponding cDNA probes. In c ontrast, using similar techniques PAI-1 and uPA-R antigens and messeng er RNAs could not be detected in normal kidneys. In both renal thrombo tic microangiopathy and normal kidneys, t-PA mRNA was detected in larg e amounts in all glomeruli and in vascular endothelial cells, but t-PA antigen was only detected in a limited number of glomerular and arter ial endothelial cells, whereas it was strongly expressed by all venous endothelial cells. Although u-PA antigen was found in almost all tubu lar sections, u-PA mRNA was only found in tubular epithelial cells in the deep cortex and the outer medulla. Our results indicate that there is an up-regulation of PAI-1 and u-PA-R expression in the glomeruli a nd in the arterial walls of thrombotic microangiopathy. The local rele ase of PAI-1 could play a role in the persistancy of fibrin deposition and the further development of fibrotic lesions. Whether uPA-R plays a pathogenic role in the development of glomerular and vascular lesion s, or is involved in the repair process of these lesions, remains to b e elucidated.