Prorenin and the heart : the Mannose 6-phosphate connection

The knowledge concerning the formation of angiotensins at cardiac tissue sites in relation to the presence and origin of cardiac renin, angiotensinogen and ACE is evaluated in chapter 2. To gain insight in the functional importance of locally generated angiotensin 11, the response of human forearm blood flow to infusion of either angiotensin I or angiotensin 11 was investigated (Chapter 3). To extend our results in the perfused isolated rat heart,31 experiments were performed to detect de novo synthesis of RAS components by neonatal rat cardiomyocytes and -fibroblasts under basal conditions and after stretch (Chapter 4). In addition, we characterized the binding and activation of human recombinant prorenin via mannose 6- phosphate/IGF11 receptors on the surface of human endothelial cells, and neonatal rat cardiomyocytes and -fibroblasts (Chapters 5 and 6). To validate our results obtained with human recombinant prorenin, neonatal rat cardiomyocytes were also incubated with human (pro)renin- containing body fluids (Chapter 7). The latter studies also addressed the importance of soluble mannose 6-phosphate/IGF11 receptors. Finally, since 1) under certain conditions man nose 6-phosphate/IGF11 receptor activation initiates transcellu\ar signaling pathways,'2 and 2) renin binding to glomerular mesangial cells leads to plasminogen activator inhibitor type-1 release and an increase in 3H-thymidine incorporation,25 we investigated whether prorenin binding and/or uptake by rat cardiomyocytes, in the presence or absence of angiotensinogen, resulted in a cellular response (Chapter 8). In these latter studies we also investigated intra- and extracellular angiotensin 11 generation and compared the effects of prorenin with those obtained with angiotensin II in parallel experiments.

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