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Angiotensin II stimulates fibronectin protein synthesis via a G??/arachidonic acid-dependent pathway.

ABSTRACT: In rabbit proximal tubular cells, ANG II type 2-receptor (AT2)-induced arachidonic acid release is PLA2 coupled and dependent of G protein ?? (G??) subunits. Moreover, ANG II activates ERK1/2 and transactivates 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?? subunits directly increased fibronectin protein expression, and this increase was inhibited by overexpression of ?-adrenergic receptor kinase (?ARK)-ct or DN-Src. Moreover, ANG II-induced fibronectin protein expression was significantly abrogated by the AT2 receptor antagonist PD123319. In addition, inhibition of cystolic PLA2 diminished ANG II-induced fibronectin expression. Endogenous arachidonic acid mimicked ANG II-induced fibronectin expression. We also found that overexpression of G?? subunits induced c-Src, ERK1/2, and EGFR tyrosine phosphorylation, which can be inhibited by overexpression of ?ARK-ct or DN-Src. G?? also induced c-Src SH2 domain association with the EGFR. Supporting these findings, in rabbit proximal tubular epithelium, immunoblot analysis indicated that ?? expression was significant. Interestingly, arachidonic acid- and eicosatetraenoic acid-induced responses were preserved in the presence of ?ARK-ct. This is the first report demonstrating the regulation of EGFR, ERK1/2, c-Src, and fibronectin by G?? subunits in renal epithelial cells. Moreover, this work demonstrates a role for G?? heterotrimeric proteins in ANG II, but not arachidonic acid, signaling in renal epithelial cells.

SUBMITTER: Alexander LD

PROVIDER: S-EPMC4121571 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Angiotensin II stimulates fibronectin protein synthesis via a Gβγ/arachidonic acid-dependent pathway.

Alexander Larry D LD Ding Yaxian Y Alagarsamy Suganthi S Cui Xiaolan X

American journal of physiology. Renal physiology 20140611 3

In rabbit proximal tubular cells, ANG II type 2-receptor (AT2)-induced arachidonic acid release is PLA2 coupled and dependent of G protein βγ (Gβγ) subunits. Moreover, ANG II activates ERK1/2 and transactivates 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 pa ...[more]

PMID: 24920755

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Project description:Cellular responses to epidermal growth factor (EGF) are dependent on the tyrosine-specific protein kinase activity of the cell-surface EGF receptor. Previous studies using WB rat liver epithelial cells have detected at least 10 proteins whose phosphotyrosine (P-Tyr) content is increased by EGF. In this study, we have examined alternate modes of activating tyrosine phosphorylation. Treatment of WB cells with hormones linked to Ca2+ mobilization and protein kinase C (PKC) activation, including angiotensin II, [Arg8]vasopressin, or epinephrine, stimulated rapid (less than or equal to 15-s) and transient increases in the P-Tyr content of several proteins (p120/125, p75/78, and p66). These proteins, detected by anti-P-Tyr immunoblotting, were similar in molecular weight to a subset of EGF-sensitive P-Tyr-containing proteins (P-Tyr-proteins). The increased P-Tyr content was confirmed by [32P]phosphoamino acid analysis of proteins recovered by anti-P-Tyr immunoprecipitation. Elevating intracellular [Ca2+] with the ionophore A23187 or ionomycin or with the tumor promoter thapsigargin mimicked the effects of hormones on tyrosine phosphorylation, whereas treatment with a PKC-activating phorbol ester did not. In addition, responses to angiotensin II were not diminished in PKC-depleted cells. Ca2+ mobilization, measured by fura-2 fluorescence, was coincident with the increase in tyrosine phosphorylation in response to angiotensin II or thapsigargin. Loading cells with the intracellular Ca2+ chelator bis-(o-aminophenoxy)ethane-N ,N ,N' , N'-tetraacetic acid (BAPTA) inhibited the appearance of all P-Tyr-proteins in response to angiotensin II, thapsigargin, or ionophores, as well as two EGF-stimulated P-Tyr-proteins. The majority of EGF-stimulated P-Tyr-proteins were not affected by BAPTA. These studies indicate that angiotensin II can alter protein-tyrosine phosphorylation in a manner that is secondary to, and apparently dependent on, Ca2+ mobilization. Thus, ligands such as EGF and angiotensin II, which act through distinct types of receptors, may activate secondary pathways involving tyrosine phosphorylation. These results also raise the possibility that certain growth-promoting effects of Ca2+ -mobilizing agents such as angiotensin II may be mediated via tyrosine phosphorylation.

Dataset Information

Angiotensin II stimulates fibronectin protein synthesis via a G??/arachidonic acid-dependent pathway.

Publications

Angiotensin II stimulates fibronectin protein synthesis via a Gβγ/arachidonic acid-dependent pathway.

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