Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition

T Oikawa, M Freeman, W Lo, DE Vaughan, A Fogo - Kidney international, 1997 - Elsevier
T Oikawa, M Freeman, W Lo, DE Vaughan, A Fogo
Kidney international, 1997Elsevier
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
endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major
physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of
fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney …
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 endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (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 PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AURA, L158,809) markedly reduced glomerular lesions (thrombosis, 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 AURA, respectively, all P < 0.01 vs. untreated). Further, ACEI and AURA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AURA, 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 affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.
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