Renin- and prorenin-induced effects in rat vascular smooth muscle cells overexpressing the human (pro)renin receptor: does (pro)renin-(pro)renin receptor interaction actually occur?

Hypertension. 2011 Dec;58(6):1111-9. doi: 10.1161/HYPERTENSIONAHA.111.180737. Epub 2011 Oct 24.


Renin/prorenin binding to the (pro)renin receptor ([P]RR) results in direct (angiotensin-independent) second-messenger activation in vitro, whereas in vivo studies in rodents overexpressing prorenin (≈400-fold) or the (P)RR do not support such activation. To solve this discrepancy, DNA synthesis, extracellular signal-regulated kinase 1/2 phosphorylation, and plasminogen-activator inhibitor 1 release were evaluated in wild-type and human (P)RR-overexpressing vascular smooth muscle cells after their incubation with 1 to 80 nmol/L of (pro)renin. Human prorenin (4 nmol/L, ie, ≈800-fold above normal) + angiotensinogen increased DNA synthesis in human (P)RR cells only in an angiotensin II type 1 receptor-dependent manner. Prorenin at this concentration also increased plasminogen-activator inhibitor 1 release via angiotensin. Prorenin alone at 4 nmol/L was without effect, but at 20 nmol/L (≈4000-fold above normal) it activated extracellular signal-regulated kinase 1/2 directly (ie, independent of angiotensin). Renin at concentrations of 1 nmol/L (≈2000-fold above normal) and higher directly stimulated DNA synthesis, extracellular signal-regulated kinase 1/2 phosphorylation, and plasminogen-activator inhibitor 1 release in wild-type and human (P)RR cells, and similar effects were seen for rat renin, indicating that they were mediated via the rat (P)RR. In conclusion, angiotensin generation depending on prorenin-(P)RR interaction may occur in transgenic rodents overexpressing prorenin several 100-fold. Direct (pro)renin-induced effects via the (P)RR require agonist concentrations that are far above the levels in wild-type and transgenic rats. Therefore, only prorenin (and not [P]RR) overexpression will result in an angiotensin-dependent phenotype, and direct renin-(P)RR interaction is unlikely to ever occur in nonrenin-synthesizing organs.

MeSH terms

  • Angiotensinogen / biosynthesis
  • Animals
  • Cells, Cultured
  • DNA Replication / drug effects
  • Dimerization
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / metabolism*
  • Phosphorylation / drug effects
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Prorenin Receptor
  • Protein Interaction Mapping
  • Protein Processing, Post-Translational / drug effects
  • Rats
  • Rats, Transgenic
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / physiology*
  • Recombinant Fusion Proteins / physiology
  • Renin / pharmacology*


  • Plasminogen Activator Inhibitor 1
  • Receptors, Cell Surface
  • Recombinant Fusion Proteins
  • Angiotensinogen
  • Extracellular Signal-Regulated MAP Kinases
  • Renin
  • Prorenin Receptor