Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway.
BACKGROUND
It is widely acknowledged that the (pro)renin receptor mediates angiotensin (Ang) II-dependent and Ang II-independent effects of prorenin.


METHODS
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.


CONCLUSIONS
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.
Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
Gang
G
Liu
Hirofumi
H
Hitomi
Naohisa
N
Hosomi
Yuki
Y
Shibayama
Daisuke
D
Nakano
Hideyasu
H
Kiyomoto
Hong
H
Ma
Yasuyoshi
Y
Yamaji
Masakazu
M
Kohno
Atsuhiro
A
Ichihara
Hiroshi
H
Itoh
Akira
A
Nishiyama
D000818:Animals; D006332:Cardiomegaly; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D012083:Renin / Q000502:physiology*; D015398:Signal Transduction
D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D012083:Renin