RGD Reference Report - Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition. - Rat Genome Database

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

Authors: Oikawa, T  Freeman, M  Lo, W  Vaughan, D E  Fogo, A 
Citation: Oikawa T, etal., Kidney Int. 1997 Jan;51(1):164-72.
RGD ID: 12880012
Pubmed: PMID:8995730   (View Abstract at PubMed)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Radiation Nephropathy treatmentISOAce (Rattus norvegicus)12880012; 12880012 RGD 
Radiation Nephropathy treatmentIMP 12880012 RGD 
Radiation Nephropathy treatmentISOSerpine1 (Rattus norvegicus)12880012; 12880012 RGD 
Radiation Nephropathy treatmentIEP 12880012 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ace  (angiotensin I converting enzyme)
Serpine1  (serpin family E member 1)

Genes (Mus musculus)
Ace  (angiotensin I converting enzyme)
Serpine1  (serine (or cysteine) peptidase inhibitor, clade E, member 1)

Genes (Homo sapiens)
ACE  (angiotensin I converting enzyme)
SERPINE1  (serpin family E member 1)


Additional Information