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

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.

• Authors: Gang Liu, Hirofumi Hitomi, Naohisa Hosomi, Yuki Shibayama, Daisuke Nakano, Hideyasu Kiyomoto, Hong Ma, Yasuyoshi Yamaji, Masakazu Kohno, Atsuhiro Ichihara, Hiroshi Itoh, Akira Nishiyama
• Journal: Journal of hypertension (J Hypertens) Vol. 29 Issue 4 Pg. 696-705 (Apr 2011) ISSN: 1473-5598 [Electronic] Netherlands
• PMID: 21252698 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• Renin

Topics

• Animals
• Cardiomegaly
• Cell Proliferation
• Cells, Cultured
• Enzyme Activation
• ErbB Receptors (physiology)
• Muscle, Smooth, Vascular (physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Renin (physiology)
• Signal Transduction