MODULATION OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN-VIVO - A NEW MECHANISM FOR THE ANTI-FIBROTIC EFFECT OF RENIN-ANGIOTENSIN INHIBITION

We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endo thelial injury and sclerosis following radiation injury in the rat. PA I-1 is a major physiological inhibitor of the plasminogen activator (P A)/plasmin system, a key regulator of fibrinolysis and extracellular m atrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P<0.001 vs. normal control). In situ hybridization revealed significant association of PA I-1 expression with sites of glomerular injury (signal intensity in in jured vs. intact glomeruli, P<0.001). Angiotensin converting enzyme in hibitors (ACEI, captopril or enalapril) or angiotensin II receptor ant agonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombo sis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4 + scale, 0. 49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0. 02 in captopril, enalapril and AIIRA, respectively, all P<0.01 vs. unt reated). further, ACEI and AIIRA markedly attenuated increased PAI-1 m RNA expression in the irradiated kidney (36, 19 and 20% expression, re spectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P<0.05, <0.01, <0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was af fected by these interventions. Thus, we speculate that inhibition of t he renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, vi a suppression of PAI-1 expression. In summary, inhibition of Ang II, i n addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/ thrombotic injury.