Angiotensin II stimulates fibronectin protein synthesis via a G beta gamma/arachidonic acid-dependent pathway

作者：Alexander Larry D^*; Ding Yaxian; Alagarsamy Suganthi; Cui Xiaolan

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2014, 307(3): F287-F302.

DOI：10.1152/ajprenal.00094.2014

• arachidonic acid
• angiotensin II
• c-Src, epidermal growth factor receptor transactivation
• carboxyl terminus of beta-adrenergic receptor kinase-1
• mitogen-activated protein kinase
• G beta gamma

In rabbit proximal tubular cells, ANG II type 2-receptor (AT(2))-induced arachidonic acid release is PLA(2) coupled and dependent of G protein beta gamma (G beta gamma) subunits. Moreover, ANG II activates ERK1/2 and trans-activates EGFR via a c-Src-dependent mechanism. Arachidonic acid has been shown to mimic this effect, at least in part, by an undetermined mechanism. In this study, we determined the effects of ANG II on fibronectin expression in cultured rabbit proximal tubule cells and elucidated the signaling pathways associated with such expression. We found that ANG II and transfection of G beta gamma subunits directly increased fibronectin protein expression, and this increase was inhibited by overexpression of beta-adrenergic receptor kinase (beta ARK)-ct or DN-Src. Moreover, ANG II-induced fibronectin protein expression was significantly abrogated by the AT(2) receptor antagonist PD123319. In addition, inhibition of cystolic PLA(2) diminished ANG II-induced fibronectin expression. Endogenous arachidonic acid mimicked ANG II-induced fibronectin expression. We also found that overexpression of G beta gamma subunits induced c-Src, ERK1/2, and EGFR tyrosine phosphorylation, which can be inhibited by overexpression of beta ARK-ct or DN-Src. G beta gamma also induced c-Src SH2 domain association with the EGFR. Supporting these findings, in rabbit proximal tubular epithelium, immunoblot analysis indicated that beta gamma expression was significant. Interestingly, arachidonic acid- and eicosatetraenoic acid-induced responses were preserved in the presence of beta ARK-ct. This is the first report demonstrating the regulation of EGFR, ERK1/2, c-Src, and fibronectin by G beta gamma subunits in renal epithelial cells. Moreover, this work demonstrates a role for G beta gamma heterotrimeric proteins in ANG II, but not arachidonic acid, signaling in renal epithelial cells.

• 出版日期2014-8-1