Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells

Yves Gorin, Jill M. Ricono, Brent Wagner, Nam Ho Kim, Basant Bhandari, Goutam Ghosh Choudhury, Hanna E. Abboud

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Angiotensin II (Ang II) stimulates hypertrophy of glomerular mesangial cells. The signalling mechanism by which Ang II exerts this effect is not precisely known. Downstream potential targets of Ang II are the extracellular-signal-regulated kinases 1 and 2 (ERK1/ERK2). We demonstrate that Ang II activates ERK1/ ERK2 via the AT1 receptor. Arachidonic acid (AA) mimics the action of Ang II on ERK1/ERK2 and phospholipase A2 inhibitors blocked Ang II-induced ERK1/ERK2 activation. The antioxidant N-acetylcysteine as well as the NAD(P)H oxidase inhibitors diphenylene iodonium and phenylarsine oxide abolished both Ang II- and AA-induced ERK1/ERK2 activation. Moreover, dominant-negative Rac1 (N17Rac1) blocks activation of ERK1/ERK2 in response to Ang II and AA, whereas constitutively active Rac1 resulted in an increase in ERK1/ERK2 activity. Antisense oligonucleotides for Nox4 NAD(P)H oxidase significantly reduce activation of ERK1/ERK2 by Ang II and AA. We also show that protein synthesis in response to Ang II and AA is inhibited by N17Rac1 or MEK (mitogen-activated protein kinase/ERK kinase) inhibitor. These results demonstrate that Ang II stimulates ERK1/ ERK2 by AA and Nox4-derived reactive oxygen species, suggesting that these molecules act as downstream signal transducers of Ang II in the signalling pathway linking the Ang II receptor AT1 to ERK1/ERK2 activation. This pathway involving AA, Rac1, Nox4, reactive oxygen species and ERK1/ERK2 may play an important role in Ang II-induced mesangial cell hypertrophy.

Original languageEnglish (US)
Pages (from-to)231-239
Number of pages9
JournalBiochemical Journal
Volume381
Issue number1
DOIs
StatePublished - Jul 1 2004

Keywords

  • Angiotensin II
  • Arachidonic acid
  • Extracellular-signal-regulated kinase 1 and 2 (ERK1/ERK2)
  • Hypertrophy
  • Nox4 NADPH oxidase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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