Prorenin Induces Intracellular Signaling in Cardiomyocytes Independently of Angiotensin II

• DOI: 10.1161/01.hyp.0000240064.19301.1b
• Publication Date: 2006-08-29T02:10:49Z
• Authors: Jasper J. Saris; Peter A.C. ’t Hoen; Ingrid M. Garrelds; Dick H.W. Dekkers; Johan T. den Dunnen; Jos M.J. Lamers; A.H. Jan Danser
• Keywords: HSP27 Heat-Shock Proteins; EMC COEUR-01-43-01; Receptors, Cell Surface; 03 medical and health sciences; 0302 clinical medicine; Plasminogen Activator Inhibitor 1; Animals; Humans; Myocytes, Cardiac; Rats, Wistar; EMC MGC-02-96-01; Cells, Cultured; Heat-Shock Proteins; Enzyme Precursors; Angiotensin II; Gene Expression Profiling; Intracellular Membranes; Neoplasm Proteins; Rats; 3. Good health; Enzyme Activation; Actin Cytoskeleton; Gene Expression Regulation; Mitogen-Activated Protein Kinases; Chymosin

Tissue accumulation of circulating prorenin results in angiotensin generation, but could also, through binding to the recently cloned (pro)renin receptor, lead to angiotensin-independent effects, like p42/p44 mitogen-activated protein kinase (MAPK) activation and plasminogen-activator inhibitor (PAI)-1 release. Here we investigated whether prorenin exerts angiotensin-independent effects in neonatal rat cardiomyocytes. Polyclonal antibodies detected the (pro)renin receptor in these cells. Prorenin affected neither p42/p44 MAPK nor PAI-1. PAI-1 release did occur during coincubation with angiotensinogen, suggesting that this effect is angiotensin mediated. Prorenin concentration-dependently activated p38 MAPK and simultaneously phosphorylated HSP27. The latter phosphorylation was blocked by the p38 MAPK inhibitor SB203580. Rat microarray gene (n=4800) transcription profiling of myocytes stimulated with prorenin detected 260 regulated genes ( P <0.001 versus control), among which genes downstream of p38 MAPK and HSP27 involved in actin filament dynamics and ( cis -)regulated genes confined in blood pressure and diabetes QTL regions, like Syntaxin-7 , were overrepresented. Quantitative real-time RT-PCR of 7 selected genes ( Opg , Timp1 , Best5 , Hsp27 , pro-Anp , Col3a1 , and Hk2 ) revealed temporal regulation, with peak levels occurring after 4 hours of prorenin exposure. This regulation was not altered in the presence of the renin inhibitor aliskiren or the angiotensin II type 1 receptor antagonist eprosartan. Finally, pilot 2D proteomic differential display experiments revealed actin cytoskeleton changes in cardiomyocytes after 48 hours of prorenin stimulation. In conclusion, prorenin exerts angiotensin-independent effects in cardiomyocytes. Prorenin-induced stimulation of the p38 MAPK/HSP27 pathway, resulting in alterations in actin filament dynamics, may underlie the severe cardiac hypertrophy that has been described previously in rats with hepatic prorenin overexpression.