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(Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells

Mariyo Sakoda1, Atsuhiro Ichihara, Yuki Kaneshiro

  • 1Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Hypertension Research : Official Journal of the Japanese Society of Hypertension
|February 6, 2008
PubMed

Insights

Prorenin activates ERK signaling in human vascular smooth muscle cells via the (pro)renin receptor, independent of angiotensin II. This pathway presents a potential therapeutic target for vascular complications.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Cell Signaling

Background:

  • The (pro)renin receptor's role in intracellular signaling is crucial, particularly in vascular complications.
  • Previous studies in mice suggest benefits of (pro)renin receptor blockade in diabetic conditions.

Purpose of the Study:

  • To elucidate the mechanism by which the human (pro)renin receptor activates mitogen-activated protein kinases (MAPKs) in human vascular smooth muscle cells (hVSMCs).
  • To investigate the signaling pathway downstream of prorenin activation in hVSMCs.

Main Methods:

  • Treatment of hVSMCs with recombinant human prorenin.
  • Assessment of MAPK activation (ERK, p38, JNK) using specific inhibitors (genistein, U0126, imidaprilat, candesartan).
  • Human (pro)renin receptor knockdown using small interfering RNA (siRNA).

Main Results:

  • Prorenin dose- and time-dependently enhanced hVSMC proliferation and activated extracellular-signal-related protein kinase (ERK).
  • ERK activation was mediated by tyrosine kinase and MEK, independent of angiotensin II or its receptor.
  • siRNA-mediated knockdown of the (pro)renin receptor significantly inhibited prorenin-induced ERK activation.

Conclusions:

  • Prorenin stimulates ERK phosphorylation in hVSMCs via the (pro)renin receptor, activating tyrosine kinase and MEK.
  • This signaling pathway operates independently of the renin-angiotensin system.
  • The (pro)renin receptor-mediated ERK pathway represents a novel therapeutic target for vascular complications.

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