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 < 1.001 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 (AIIRA, 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 AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, 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 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.
Oikawa
T
T
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Freeman
M
M
Lo
W
W
Vaughan
D E
DE
Fogo
A
A
D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics; D004656:Enalapril / Q000494:pharmacology; D005337:Fibrin / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006133:Growth Substances / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D017403:In Situ Hybridization; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011507:Proteinuria / Q000188:drug therapy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects / Q000528:radiation effects; D012083:Renin / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy; D010959:Tissue Plasminogen Activator / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000092502:Renin Inhibitors
D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002216:Captopril; D016207:Cytokines; D004656:Enalapril; D005337:Fibrin; D005341:Fibrinolysin; D006133:Growth Substances; D007093:Imidazoles; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D012083:Renin; D013777:Tetrazoles; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D014662:Vasoconstrictor Agents; D000092502:Renin Inhibitors; C070967:L 158809