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

Mariyo Sakoda, Atsuhiro Ichihara, Yuki Kaneshiro, Tomoko Takemitsu, Yuichi Nakazato, A. H M Nurun Nabi, Tsutomu Nakagawa, Fumiaki Suzuki, Tadashi Inagami, Hiroshi Itoh

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Blockade of (pro)renin receptor has benefits in diabetic anglotensin II type-1a-receptor-deficient mice, suggesting the importance of (pro)renin receptor-mediated intracellular signals. To determine the mechanism whereby the human (pro)renin receptor activates mitogen-activated protein kinases in human vascular smooth muscle cells (hVSMC), we treated the cells with recombinant human prorenin. Prorenin enhanced hVSMC proliferation and activated extracellular-signal-related protein kinase (ERK) in a dose- and time-dependent manner but did not influence activation of p38 or c-Jun NH2-terminal kinase. The activated ERK level was reduced to the control level by the tyrosine kinase inhibitor genistein, and the MEK inhibitor U0126 markedly reduced the activated ERK level to the control level, whereas the level of activated ERK was unaffected by the angiotensin-converting enzyme inhibitor imidaprilat or the angiotensin II receptor blocker candesartan. A human (pro)renin receptor was present in hVSMCs, and its knockdown with small interfering RNA (siRNA) significantly inhibited the prorenin-induced ERK activation. These results suggest that prorenin stimulates ERK phosphorylation in hVSMCs through the receptor-mediated activation of tyrosine kinase and subsequently MEK, independently of the generation of angiotensin II or the activation of its receptor. The (pro)renin receptor-mediated ERK signal transduction is thus a possible new therapeutic target for preventing vascular complications.

Original languageEnglish
Pages (from-to)1139-1146
Number of pages8
JournalHypertension Research
Volume30
Issue number11
DOIs
Publication statusPublished - 2007 Nov

Fingerprint

Mitogen-Activated Protein Kinases
Vascular Smooth Muscle
Renin
Protein Kinases
Smooth Muscle Myocytes
Mitogen-Activated Protein Kinase Kinases
imidaprilat
Protein-Tyrosine Kinases
JNK Mitogen-Activated Protein Kinases
Genistein
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Angiotensin II
Small Interfering RNA
Blood Vessels
Signal Transduction
Phosphorylation
Cell Proliferation

Keywords

  • Extracellular-signal-related protein kinase
  • Prorenin
  • Receptor
  • Small interfering RNA
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Internal Medicine

Cite this

(Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells. / Sakoda, Mariyo; Ichihara, Atsuhiro; Kaneshiro, Yuki; Takemitsu, Tomoko; Nakazato, Yuichi; Nabi, A. H M Nurun; Nakagawa, Tsutomu; Suzuki, Fumiaki; Inagami, Tadashi; Itoh, Hiroshi.

In: Hypertension Research, Vol. 30, No. 11, 11.2007, p. 1139-1146.

Research output: Contribution to journalArticle

Sakoda, M, Ichihara, A, Kaneshiro, Y, Takemitsu, T, Nakazato, Y, Nabi, AHMN, Nakagawa, T, Suzuki, F, Inagami, T & Itoh, H 2007, '(Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells', Hypertension Research, vol. 30, no. 11, pp. 1139-1146. https://doi.org/10.1291/hypres.30.1139
Sakoda, Mariyo ; Ichihara, Atsuhiro ; Kaneshiro, Yuki ; Takemitsu, Tomoko ; Nakazato, Yuichi ; Nabi, A. H M Nurun ; Nakagawa, Tsutomu ; Suzuki, Fumiaki ; Inagami, Tadashi ; Itoh, Hiroshi. / (Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells. In: Hypertension Research. 2007 ; Vol. 30, No. 11. pp. 1139-1146.
@article{287bf6fc2d6c4cfa93c4c5ba020725f4,
title = "(Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells",
abstract = "Blockade of (pro)renin receptor has benefits in diabetic anglotensin II type-1a-receptor-deficient mice, suggesting the importance of (pro)renin receptor-mediated intracellular signals. To determine the mechanism whereby the human (pro)renin receptor activates mitogen-activated protein kinases in human vascular smooth muscle cells (hVSMC), we treated the cells with recombinant human prorenin. Prorenin enhanced hVSMC proliferation and activated extracellular-signal-related protein kinase (ERK) in a dose- and time-dependent manner but did not influence activation of p38 or c-Jun NH2-terminal kinase. The activated ERK level was reduced to the control level by the tyrosine kinase inhibitor genistein, and the MEK inhibitor U0126 markedly reduced the activated ERK level to the control level, whereas the level of activated ERK was unaffected by the angiotensin-converting enzyme inhibitor imidaprilat or the angiotensin II receptor blocker candesartan. A human (pro)renin receptor was present in hVSMCs, and its knockdown with small interfering RNA (siRNA) significantly inhibited the prorenin-induced ERK activation. These results suggest that prorenin stimulates ERK phosphorylation in hVSMCs through the receptor-mediated activation of tyrosine kinase and subsequently MEK, independently of the generation of angiotensin II or the activation of its receptor. The (pro)renin receptor-mediated ERK signal transduction is thus a possible new therapeutic target for preventing vascular complications.",
keywords = "Extracellular-signal-related protein kinase, Prorenin, Receptor, Small interfering RNA, Vascular smooth muscle cells",
author = "Mariyo Sakoda and Atsuhiro Ichihara and Yuki Kaneshiro and Tomoko Takemitsu and Yuichi Nakazato and Nabi, {A. H M Nurun} and Tsutomu Nakagawa and Fumiaki Suzuki and Tadashi Inagami and Hiroshi Itoh",
year = "2007",
month = "11",
doi = "10.1291/hypres.30.1139",
language = "English",
volume = "30",
pages = "1139--1146",
journal = "Hypertension Research",
issn = "0916-9636",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - (Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells

AU - Sakoda, Mariyo

AU - Ichihara, Atsuhiro

AU - Kaneshiro, Yuki

AU - Takemitsu, Tomoko

AU - Nakazato, Yuichi

AU - Nabi, A. H M Nurun

AU - Nakagawa, Tsutomu

AU - Suzuki, Fumiaki

AU - Inagami, Tadashi

AU - Itoh, Hiroshi

PY - 2007/11

Y1 - 2007/11

N2 - Blockade of (pro)renin receptor has benefits in diabetic anglotensin II type-1a-receptor-deficient mice, suggesting the importance of (pro)renin receptor-mediated intracellular signals. To determine the mechanism whereby the human (pro)renin receptor activates mitogen-activated protein kinases in human vascular smooth muscle cells (hVSMC), we treated the cells with recombinant human prorenin. Prorenin enhanced hVSMC proliferation and activated extracellular-signal-related protein kinase (ERK) in a dose- and time-dependent manner but did not influence activation of p38 or c-Jun NH2-terminal kinase. The activated ERK level was reduced to the control level by the tyrosine kinase inhibitor genistein, and the MEK inhibitor U0126 markedly reduced the activated ERK level to the control level, whereas the level of activated ERK was unaffected by the angiotensin-converting enzyme inhibitor imidaprilat or the angiotensin II receptor blocker candesartan. A human (pro)renin receptor was present in hVSMCs, and its knockdown with small interfering RNA (siRNA) significantly inhibited the prorenin-induced ERK activation. These results suggest that prorenin stimulates ERK phosphorylation in hVSMCs through the receptor-mediated activation of tyrosine kinase and subsequently MEK, independently of the generation of angiotensin II or the activation of its receptor. The (pro)renin receptor-mediated ERK signal transduction is thus a possible new therapeutic target for preventing vascular complications.

AB - Blockade of (pro)renin receptor has benefits in diabetic anglotensin II type-1a-receptor-deficient mice, suggesting the importance of (pro)renin receptor-mediated intracellular signals. To determine the mechanism whereby the human (pro)renin receptor activates mitogen-activated protein kinases in human vascular smooth muscle cells (hVSMC), we treated the cells with recombinant human prorenin. Prorenin enhanced hVSMC proliferation and activated extracellular-signal-related protein kinase (ERK) in a dose- and time-dependent manner but did not influence activation of p38 or c-Jun NH2-terminal kinase. The activated ERK level was reduced to the control level by the tyrosine kinase inhibitor genistein, and the MEK inhibitor U0126 markedly reduced the activated ERK level to the control level, whereas the level of activated ERK was unaffected by the angiotensin-converting enzyme inhibitor imidaprilat or the angiotensin II receptor blocker candesartan. A human (pro)renin receptor was present in hVSMCs, and its knockdown with small interfering RNA (siRNA) significantly inhibited the prorenin-induced ERK activation. These results suggest that prorenin stimulates ERK phosphorylation in hVSMCs through the receptor-mediated activation of tyrosine kinase and subsequently MEK, independently of the generation of angiotensin II or the activation of its receptor. The (pro)renin receptor-mediated ERK signal transduction is thus a possible new therapeutic target for preventing vascular complications.

KW - Extracellular-signal-related protein kinase

KW - Prorenin

KW - Receptor

KW - Small interfering RNA

KW - Vascular smooth muscle cells

UR - http://www.scopus.com/inward/record.url?scp=37849044605&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37849044605&partnerID=8YFLogxK

U2 - 10.1291/hypres.30.1139

DO - 10.1291/hypres.30.1139

M3 - Article

VL - 30

SP - 1139

EP - 1146

JO - Hypertension Research

JF - Hypertension Research

SN - 0916-9636

IS - 11

ER -