Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II

Hypertension. 2006 Oct;48(4):564-71. doi: 10.1161/01.HYP.0000240064.19301.1b. Epub 2006 Aug 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / physiology
  • Angiotensin II / pharmacology
  • Angiotensin II / physiology*
  • Animals
  • Cells, Cultured
  • Chymosin
  • Enzyme Activation
  • Enzyme Precursors
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • HSP27 Heat-Shock Proteins
  • Heat-Shock Proteins / metabolism
  • Humans
  • Intracellular Membranes / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Myocytes, Cardiac / metabolism*
  • Neoplasm Proteins / metabolism
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Cell Surface / metabolism
  • Recombinant Proteins / pharmacology
  • Renin / metabolism
  • Renin / pharmacology
  • Renin / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*


  • Enzyme Precursors
  • HSP27 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Hspb1 protein, rat
  • Neoplasm Proteins
  • Plasminogen Activator Inhibitor 1
  • Receptors, Cell Surface
  • Recombinant Proteins
  • Angiotensin II
  • Mitogen-Activated Protein Kinases
  • prorennin
  • Renin
  • Chymosin