Effect of the plasminogen-plasmin system on hypertensive renal and cardiac damage

Benjamin Knier, Nada Cordasic, Bernd Klanke, Juliane Heusinger-Ribeiro, Christoph Daniel, Roland Veelken, Andrea Hartner, Karl F Hilgers
Journal of Hypertension 2011, 29 (8): 1602-12

BACKGROUND: The plasminogen-plasmin system affects tissue fibrosis, presumably by interacting with metalloproteinases (MMPs) and macrophage recruitment. This study tests the influence of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPa) on angiotensin II-mediated hypertensive kidney and heart injury.

METHOD: Hypertension was induced by continuous angiotensin II (Ang II) infusion via osmotic mini-pumps over 4 weeks. The effects of Ang II infusion were determined in mice lacking PAI-1 (PAI-1), mice lacking tPa (tPa), and wild-type mice. Normotensive mice of the respective genotype served as controls. Blood pressure was recorded by continuous radiotelemetric intra-arterial measurements.

RESULTS: Ang II infusion significantly enhanced arterial blood pressure in all groups. However, the increase in blood pressure was more pronounced in the tPa group. Albuminuria was highest in hypertensive wild-type compared to the other Ang II-infused groups. Hypertensive PAI-1 mice exhibited less glomerulosclerosis, higher nephrin immunostaining, and lower renal interstitial collagen I deposition. Gelatin zymography revealed higher activity of MMP-2 in hypertensive PAI-1, whereas no differences were observed in macrophage infiltration. tPa deficiency did not alter kidney fibrosis, although hypertensive tPa revealed less renal expression of fibrotic genes, less macrophage infiltration, and reduced MMP-2 activity. On the other hand, hypertension-induced fibrosis as well as macrophage infiltration in the heart was profoundly enhanced in PAI-1 mice. Fibrin staining revealed perivascular exudations in the myocardium of hypertensive PAI-1 suggesting vascular leakage.

CONCLUSION: These findings underscore the unexpectedly complex role of plasminogen activation for hypertensive target organ damage.

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