Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway

Gang Liu, Hirofumi Hitomi, Naohisa Hosomi, Yuki Shibayama, Daisuke Nakano, Hideyasu Kiyomoto, Hong Ma, Yasuyoshi Yamaji, Masakazu Kohno, Atsuhiro Ichihara, Hiroshi Itoh, Akira Nishiyama

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Background: It is widely acknowledged that the (pro)renin receptor mediates angiotensin (Ang) II-dependent and Ang II-independent effects of prorenin. METHOD: We examined the effect of prorenin on vascular smooth muscle cell (VSMC) signal transduction, proliferation, and hypertrophy. Results: Recombinant rat prorenin dose-dependently increased extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylation in rat VSMCs. Prorenin also significantly increased cell number, and [H]-thymidine and [H]-leucine incorporation, which were attenuated by pretreatment with inhibitors for ERK kinase and phosphatidylinositol 3 kinase. Prorenin was also found to stimulate epidermal growth factor (EGF) receptor and Src phosphorylation. Pretreatment of VSMCs with an EGF receptor tyrosine kinase inhibitor and a Src inhibitor significantly attenuated the prorenin-induced increase in ERK 1/2 and Akt phosphorylation, as well as DNA and protein synthesis. Prorenin-induced phosphorylation of the EGF receptor, ERK 1/2, and Akt, as well as DNA and protein synthesis were all blocked by (pro)renin receptor siRNA, but not by an Ang II type 1 receptor blocker, candesartan, nor an Ang-converting enzyme inhibitor, captopril. Conclusion: These results reveal that prorenin directly stimulates VSMC proliferative and hypertrophic changes, dependent on the (pro)renin receptor, independent of Ang II. Furthermore, EGF receptor-mediated ERK 1/2 and Akt activation contributes to prorenin-dependent proliferative and hypertrophic effects in VSMCs.

Original languageEnglish
Pages (from-to)696-705
Number of pages10
JournalJournal of hypertension
Volume29
Issue number4
DOIs
Publication statusPublished - 2011 Apr

Keywords

  • (pro)renin receptor
  • epidermal growth factor receptor
  • prorenin
  • vascular smooth muscle cell

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Liu, G., Hitomi, H., Hosomi, N., Shibayama, Y., Nakano, D., Kiyomoto, H., Ma, H., Yamaji, Y., Kohno, M., Ichihara, A., Itoh, H., & Nishiyama, A. (2011). Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway. Journal of hypertension, 29(4), 696-705. https://doi.org/10.1097/HJH.0b013e328343c62b