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

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. J Hypertens 29: 1602-1612 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.