Angiotensin II Stimulates Protein Synthesis and Inhibits Proliferation in Primary Cultures of Rat Adrenal Glomerulosa Cells

Abstract

Angiotensin II (Ang II) is one of the most important stimuli of rat adrenal glomerulosa cells. The aim of the present study was to investigate whether Ang II can stimulate cell proliferation and/or hypertrophy and investigate pathways and intracellular targets. A 3-d treatment with Ang II (5-100 nm), through the Ang II type 1 receptor subtype, abolished cell proliferation observed in control cells but increased protein synthesis. Preincubation with PD98059 (a MAPK kinase inhibitor) abolished basal proliferation and had no effect on basal protein synthesis but did reverse the effect of Ang II on protein synthesis. The p38 MAPK inhibitor SB203580 reversed the inhibitory effect on cell proliferation and abolished the increase in protein synthesis, whereas the c-Jun N-terminal kinase inhibitor SP600125 had no effect. Time-course studies revealed that Ang II stimulated phosphorylation of both p42/p44mapk and p38 MAPK but did not activate c-Jun N-terminal kinase. Ang II had no effect on the level of cyclin E expression but increased the expression of the cyclin-dependent kinase, p27Kip1, an effect abolished in cells preincubated with SB203580 and PD98059. In conclusion, in cultured rat glomerulosa cells, a 3-d treatment with Ang II increases protein synthesis, with a concomitant decrease in proliferation. These effects are mediated by both the p42/p44mapk and p38 MAPK pathways, which increase expression of the steroidogenic enzymes, steroidogenic acute regulatory protein and 3beta-hydroxysteroid dehydrogenase and p27Kip1, a protein known to block the cell cycle in G1 phase. Together these results support the key role of Ang II as a stimulus of steroid synthesis rather than a proliferating factor.

Mechanisms of adrenal gland growth: signal integration by extracellular signal regulated kinases1/2

“…In line with this provocative hypothesis, activation of ERK1/2 resulted in a growth arrest of PC12 cells and induced neuronal differentiation in that cellular system . Also in rat adrenal zona glomerulosa cells ERK1/2 activation blocked cell proliferation and stimulated steroidogenesis (Otis et al 2005, Otis & Gallo-Payet 2007. A role of ERK1/2 for functional aspects of cortical ( Wu et al 2002, Chang et al 2008 or medullary cells (Cox & Parsons 1997, Takekoshi et al 2001, Shibuya et al 2002, Yanagihara et al 2005, Shinkai et al 2007) has also been provided by others.…”

“…For the human adrenocortical carcinoma cell line H295R it has been suggested that angiotensin II stimulated mitogenesis might occur via ERK1/2 activation ( Watanabe et al 1996). By contrast, in non-malignant rat adrenal glomerulosa cells, angiotensin II mediated induction of ERK1/2 phosphorylation resulted in an inhibition of cell proliferation (Otis et al 2005). Since in the same system angiotensin II stimulated hypertrophy, protein synthesis and steroidogenesis via a mechanism involving both ERK1/2 and p38 MAPK, the effects on growth seem to be related to functional aspects of zona glomerulosa cells (Otis & Gallo-Payet 2006).…”

“…The permanent perception of diverse factors affecting adrenal growth and function argues in favor of one common intracellular target, which coordinates and integrates the different stimuli and which further represents a potent effector of central cellular responses like proliferation, survival, apoptosis, or differentiation. As a potential candidate for an intracellular target in adrenal cells extracellular signal regulated kinases 1/2 (ERK1/2) have been demonstrated to affect cell proliferation , Andreis et al 2000, Lepique et al 2000, Lotfi et al 2000, Whitworth et al 2002, Ferreira et al 2007, apoptosis (Mazzocchi et al 2004, Edwin & Patel 2008 cell survival (Ziegler et al 2006), cell migration (Ho et al 2001(Ho et al , 2005, or synthesis and secretion of cortical ( Wu et al 2002, Otis et al 2005, Kempná et al 2007, Chang et al 2008 or medullary hormones (Cox & Parsons 1997, Shibuya et al 2002. Thus, in fact, ERK1/2 have the potential and format to represent such common targets with multiple biological effects in the adrenal gland as proposed before (Chabre et al 1995).…”

Human adipocytes induce an ERK1/2 MAP kinases-mediated upregulation of steroidogenic acute regulatory protein (StAR) and an angiotensin II — sensitization in human adrenocortical cells

“…A first screen of these cells using a protein kinase array for signal transduction protein expression and phosphorylation (Figure 4) indicated the involvement of mitogen-activated protein kinases (MAPK) such as ERK1/2. In addition, it has been shown recently that in cultured rat glomerulosa cells, AngII increases protein synthesis including the expression of the steroidogenic enzymes and steroidogenic acute regulatory protein (StAR) via the p42/p44 MAPK and p38 MAPK pathways, 20 and the stimulation of hormone secretion in aldosterone-producing glomerulosa cells. 21 Therefore, the role of ERK1/2 MAPKs in fat cell-induced aldosterone secretion was determined in human H295R adrenocortical cells and isolated human adrenocortical cells in primary culture.…”

Signal transduction of the (pro)renin receptor as a novel therapeutic target for preventing end-organ damage

“…2,9 This MAPK activation after stimulation of the (P)RR with renin occurs relatively late, with a maximum described after 30 min, 2 compared with ang II stimulation experiments that peak at about 5 min. 10 In addition, Akt kinase, which itself is located downstream of PI3K, can activate MAP kinases by mechanisms involving, for example, protein kinase C and nitric oxide 11,12 (Figure 2). Therefore, we speculate that PLZF acts upstream of MAP kinases (Figure 2), which is supported by a recent publication that reports that expression of PLZF can enhance the activity of ERK kinase.…”