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J Biol Chem. 2007 Jan 9.
Skeletal muscle atrophy: A link between depression of protein synthesis and increase in degradation.
Eley HL, Tisdale MJ.
Biomedical Science, Aston University, Birmingham, West Midlands B4 7ET.
Both proteolysis-inducing factor (PIF) and angiotensin II have been shown to produce a depression in protein synthesis in murine myotubes concomitant with an increased phosphorylation of eukaryotic initiation factor 2 (eIF2alpha). Both PIF and angiotensin II were shown to induce autophosphorylation of the RNA-dependent protein kinase (PKR), and an inhibitor of this enzyme completely attenuated the depression in protein synthesis, and prevented the induction of eIF2alpha phosphorylation. The PKR inhibitor also completely attenuated the increase in protein degradation induced by PIF and angiotensin II, and prevented the increase in proteasome expression and activity. To confirm these results myotubes were transfected with plasmids that express either wild-type PKR, or a catalytically inactive PKR variant, PKRdelta6. Myotubes expressing PKRdelta6 showed no increase in eIF2alpha phosphorylation in response to PIF or angiotensin II, no depression in protein synthesis and no increase in protein degradation or increase in proteasome expression. Induction of the ubiquitin-proteasome pathway by PIF and angiotensin II has been linked to activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Inhibition of PKR prevented nuclear migration of NF-kappaB in response to both PIF and angiotensin II, by preventing degradation of the inhibitor protein I-kappaB. Phosphorylation of PKR and eIF2alpha was also significantly increased in the gastrocnemius muscle of weight losing mice bearing the MAC16 tumor, suggesting that a similar process may be operative in cancer cachexia. These results provide a link between the depression of protein synthesis in skeletal muscle and the increase in protein degradation.
Cancer Lett. 2006 Jan 18;231(2):290-4.
Angiotensin II directly inhibits protein synthesis in murine myotubes.
Russell ST, Sanders PM, Tisdale MJ.
Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, UK.
Angiotensin II (Ang II) has been implicated in muscle protein loss in cachexia. To determine whether the Ang I/II system directly inhibits protein synthesis in muscle their effect has been monitored in vitro using murine myotubes as a surrogate model system. Ang I inhibited protein synthesis by 40-50% over the concentration range of 0.05-2.5 microM within 30 min of addition, and the inhibition remained relatively constant over 24 h. The effect was attenuated by co-incubation with the angiotensin converting enzyme inhibitor imidaprilat (50 microM) suggesting that inhibition of protein synthesis was due to the formation of Ang II. Ang II also inhibited protein synthesis by 40-50% over the concentration range of 0.1-5 microM, and the inhibition also remained relatively constant between 30 min and 24 h after addition. The effect was attenuated by insulin-like growth factor-1 (IGF-1) (25-100 ng/ml). Thus, Ang I/II have the ability to induce muscle atrophy through inhibition of protein synthesis.
Cell Signal. 2006 Jul;18(7):1087-96.
Mechanism of induction of muscle protein degradation by angiotensin II.
Russell ST, Wyke SM, Tisdale MJ.
Biomolecular Sciences, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
Angiotensin I and II have been shown to directly induce protein degradation in skeletal muscle through an increased activity and expression of the ubiquitin-proteasome proteolytic pathway. This investigation determines the role of the nuclear transcription factor nuclear factor-kappaB (NF-kappaB) in this process. Using murine myotubes as a surrogate model system both angiotensin I and II were found to induce activation of protein kinase C (PKC), with a parabolic dose-response curve similar to the induction of total protein degradation. Activation of PKC was required for the induction of proteasome expression, since calphostin C, a highly specific inhibitor of PKC, attenuated both the increase in total protein degradation and in proteasome expression and functional activity increased by angiotensin II. PKC is known to activate I-kappaB kinase (IKK), which is responsible for the phosphorylation and subsequent degradation of I-kappaB. Both angiotensin I and II induced an early decrease in cytoplasmic I-kappaB levels followed by nuclear accumulation of NF-kappaB. Using an NF-kappaB luciferase construct this was shown to increase transcriptional activation of NF-kappaB regulated genes. Maximal luciferase expression was seen at the same concentrations of angiotensin I/II as those inducing protein degradation. Total protein degradation induced by both angiotensin I and II was attenuated by resveratrol, which prevented nuclear accumulation of NF-kappaB, confirming that activation of NF-kappaB was responsible for the increased protein degradation. These results suggest that induction of proteasome expression by angiotensin I/II involves a signalling pathway involving PKC and NF-kappaB.
Endocrinology. 2001 Apr;142(4):1489-96.
Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I.
Brink M, Price SR, Chrast J, Bailey JL, Anwar A, Mitch WE, Delafontaine P.
Division of Cardiology, University Hospital of Geneva, CH-1211 Geneva, Switzerland.
We previously showed that angiotensin II (ang II) infusion in the rat produces cachexia and decreases circulating insulin-like growth factor I (IGF-I). The weight loss derives from an anorexigenic response and a catabolic effect of ang II. In these experiments we assessed potential catabolic mechanisms and the involvement of the IGF-I system in these responses to ang II. Ang II infusion caused a significant decrease in body weight compared with that of pair-fed control rats. Kidney and left ventricular weights were significantly increased by ang II, whereas fat tissue was unchanged. Skeletal muscle mass was significantly decreased in the ang II-infused rats, and a reduction in lean muscle mass was a major reason for their overall loss of body weight. In skeletal muscles, ang II did not significantly decrease protein synthesis, but overall protein breakdown was accelerated; inhibiting lysosomal and calcium-activated proteases did not reduce the ang II-induced increase in muscle proteolysis. Circulating IGF-I levels were 33% lower in ang II rats vs. control rats, and this difference was reflected in lower IGF-I messenger RNA levels in the liver. Moreover, IGF-I, IGF-binding protein-3, and IGF-binding protein-5 messenger RNAs in the gastrocnemius were significantly reduced. To investigate whether the reduced circulating IGF-I accounts for the loss in muscle mass, we increased circulating IGF-I by coinfusing ang II and IGF-I, but this did not prevent muscle loss. Our data suggest that ang II causes a loss in skeletal muscle mass by enhancing protein degradation probably via its inhibitory effect on the autocrine IGF-I system.
J Clin Invest. 2005 Feb;115(2):451-8.
Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting.
Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P.
Tulane University Health Sciences Center, New Orleans, Louisiana 70112-2699, USA.
Advanced congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. We previously showed that angiotensin II infusion in rats produces cachexia secondarily to increased muscle proteolysis and also decreases levels of circulating and skeletal muscle IGF-1. Here we show that angiotensin II markedly downregulates phospho-Akt and activates caspase-3 in skeletal muscle, leading to actin cleavage, an important component of muscle proteolysis, and to increased apoptosis. These changes are blocked by muscle-specific expression of IGF-1, likely via the Akt/mTOR/p70S6K signaling pathway. We also demonstrate that mRNA levels of the ubiquitin ligases atrogin-1 and muscle ring finger-1 are upregulated in angiotensin II-infused WT, but not in IGF-1-transgenic, mice. These findings strongly suggest that angiotensin II downregulation of IGF-1 in skeletal muscle is causally related to angiotensin II-induced wasting. Because the renin-angiotensin system is activated in many catabolic conditions, our findings have broad implications for understanding mechanisms of skeletal muscle wasting and provide a rationale for new therapeutic approaches.
Br J Cancer. 2005 Aug 22;93(4):425-34.
Angiotensin II directly induces muscle protein catabolism through the ubiquitin-proteasome proteolytic pathway and may play a role in cancer cachexia.
Sanders PM, Russell ST, Tisdale MJ.
Pharmaceutical Sciences Research Institute, Aston University, Birmingham, UK.
The ability of angiotensin I (Ang I) and II (Ang II) to induce directly protein degradation in skeletal muscle has been studied in murine myotubes. Angiotensin I stimulated protein degradation with a parabolic dose-response curve and with a maximal effect between 0.05 and 0.1 microM. The effect was attenuated by coincubation with the angiotensin-converting enzyme (ACE) inhibitor imidaprilat, suggesting that angiotensin I stimulated protein degradation through conversion to Ang II. Angiotensin II also stimulated protein breakdown with a similar dose-response curve, and with a maximal effect between 1 and 2.5 microM. Total protein degradation, induced by both Ang I and Ang II, was attenuated by the proteasome inhibitors lactacystin (5 microM) and MG132 (10 microM), suggesting that the effect was mediated through upregulation of the ubiquitin-proteasome proteolytic pathway. Both Ang I and Ang II stimulated an increased proteasome 'chymotrypsin-like' enzyme activity as well as an increase in protein expression of 20S proteasome alpha-subunits, the 19S subunits MSS1 and p42, at the same concentrations as those inducing protein degradation. The effect of Ang I was attenuated by imidaprilat, confirming that it arose from conversion to Ang II. These results suggest that Ang II stimulates protein degradation in myotubes through induction of the ubiquitin-proteasome pathway. Protein degradation induced by Ang II was inhibited by insulin-like growth factor and by the polyunsaturated fatty acid, eicosapentaenoic acid. These results suggest that Ang II has the potential to cause muscle atrophy through an increase in protein degradation. The highly lipophilic ACE inhibitor imidapril (Vitortrade mark) (30 mg kg(-1)) attenuated the development of weight loss in mice bearing the MAC16 tumour, suggesting that Ang II may play a role in the development of cachexia in this model.
Peptides. 2006 Dec;27(12):3269-75.
Angiotensin II induces NF-kappaB activation in HUVEC via the p38MAPK pathway.
Guo RW, Yang LX, Li MQ, Liu B, Wang XM.
Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan 650032, China.
Angiotensin II (Ang II) is the main active peptide of the renin-angiotensin system (RAS), producing a number of inflammatory mediators that lead to endothelial dysfunction and the progression of atherosclerosis. Ang II-induced NF-kappaB nuclear translocation plays a pivotal role in this response. This study examines the NF-kappaB activation mechanism elicited by Ang II in human umbilical vein endothelial cells (HUVEC). Electrophoretic mobility shift assays and Western blotting revealed that Ang II, signaling via AT(1), produces a time-dependent increase in NF-kappaB DNA binding and IkappaBalpha degradation. These results also demonstrate that Ang II leads to MAPK phosphorylation and p38MAPK pathway-induced NF-kappaB activation. Furthermore, AT(1) is required for p38MAPK phosphorylation induced by Ang II. This study provides evidence that Ang II elicits NF-kappaB activation via the p38MAPK pathway in HUVEC.
Br J Cancer. 2005 Feb 28;92(4):711-21.
NF-kappaB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin-proteasome system in skeletal muscle.
Wyke SM, Tisdale MJ.
Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, UK.
Loss of skeletal muscle in cancer cachexia has a negative effect on both morbidity and mortality. The role of nuclear factor-kappaB (NF-kappaB) in regulating muscle protein degradation and expression of the ubiquitin-proteasome proteolytic pathway in response to a tumour cachectic factor, proteolysis-inducing factor (PIF), has been studied by creating stable, transdominant-negative, muscle cell lines. Murine C(2)C(12) myoblasts were transfected with plasmids with a CMV promoter that had mutations at the serine phosphorylation sites required for degradation of I-kappaBalpha, an NF-kappaB inhibitory protein, and allowed to differentiate into myotubes. Proteolysis-inducing factor induced degradation of I-kappaBalpha, nuclear accumulation of NF-kappaB and an increase in luciferase reporter gene activity in myotubes containing wild-type, but not mutant, I-kappaBalpha proteins. Proteolysis-inducing factor also induced total protein degradation and loss of the myofibrillar protein myosin in myotubes containing wild-type, but not mutant, plasmids at the same concentrations as those causing activation of NF-kappaB. Proteolysis-inducing factor also induced increased expression of the ubiquitin-proteasome pathway, as determined by 'chymotrypsin-like' enzyme activity, the predominant proteolytic activity of the beta-subunits of the proteasome, protein expression of 20S alpha-subunits and the 19S subunits MSS1 and p42, as well as the ubiquitin conjugating enzyme, E2(14k), in cells containing wild-type, but not mutant, I-kappaBalpha. The ability of mutant I-kappaBalpha to inhibit PIF-induced protein degradation, as well as expression of the ubiquitin-proteasome pathway, confirms that both of these responses depend on initiation of transcription by NF-kappaB.
J Biol Chem. 2006 Nov 17;281(46):35137-46.
Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells.
Wei Y, Sowers JR, Nistala R, Gong H, Uptergrove GM, Clark SE, Morris EM, Szary N, Manrique C, Stump CS.
Department of Internal Medicine, University of Missouri-Columbia 65212, USA.
The renin-angiotensin system (RAS) and reactive oxygen species (ROS) have been implicated in the development of insulin resistance and its related complications. There is also evidence that angiotensin II (Ang II)-induced generation of ROS contributes to the development of insulin resistance in skeletal muscle, although the precise mechanisms remain unknown. In the present study, we found that Ang II markedly enhanced NADPH oxidase activity and consequent ROS generation in L6 myotubes. These effects were blocked by the angiotensin II type 1 receptor blocker losartan, and by the NADPH oxidase inhibitor apocynin. Ang II also promoted the translocation of NADPH oxidase cytosolic subunits p47phox and p67phox to the plasma membrane within 15 min. Furthermore, Ang II abolished insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), activation of protein kinase B (Akt), and glucose transporter-4 (GLUT4) translocation to the plasma membrane, which was reversed by pretreating myotubes with losartan or apocynin. Finally, small interfering RNA (siRNA)-specific gene silencing targeted specifically against p47phox (p47siRNA), in both L6 and primary myotubes, reduced the cognate protein expression, decreased NADPH oxidase activity, restored Ang II-impaired IRS1 and Akt activation as well as GLUT4 translocation by insulin. These results suggest a pivotal role for NADPH oxidase activation and ROS generation in Ang II-induced inhibition of insulin signaling in skeletal muscle cells
Circ Res. 2004 May 14;94(9):1211-8.
Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells.
Andreozzi F, Laratta E, Sciacqua A, Perticone F, Sesti G.
Department of Clinical and Experimental Medicine, University Magna Graecia of Catanzaro, Italy.
It has been suggested that serine (Ser) phosphorylation of insulin receptor substrate-1 (IRS-1) decreases the ability of IRS-1 to be phosphorylated on tyrosine, thereby attenuating insulin signaling. There is evidence that angiotensin II (AII) may impair insulin signaling to the IRS-1/phosphatydilinositol 3-kinase (PI 3-kinase) pathway by enhancing Ser phosphorylation. Insulin stimulates NO production by a pathway involving IRS-1/PI3-kinase/Akt/endothelial NO synthase (eNOS). We addressed the question of whether AII affects insulin signaling involved in NO production in human umbilical vein endothelial cells and tested the hypothesis that the inhibitory effect of AII on insulin signaling was caused by increased site-specific Ser phosphorylation in IRS-1. Exposure of human umbilical vein endothelial cells to AII resulted in inhibition of insulin-stimulated production of NO. This event was associated with impaired IRS-1 phosphorylation at Tyr612 and Tyr632, two sites essential for engaging the p85 subunit of PI3-kinase, resulting in defective activation of PI 3-kinase, Akt, and eNOS. This inhibitory effect of AII was reversed by the type 1 receptor antagonist losartan. AII increased c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) 1/2 activity, which was associated with a concomitant increase in IRS-1 phosphorylation at Ser312 and Ser616, respectively. Inhibition of JNK and ERK1/2 activity reversed the negative effects of AII on insulin-stimulated NO production. Our data suggest that AII, acting via the type 1 receptor, increases IRS-1 phosphorylation at Ser312 and Ser616 via JNK and ERK1/2, respectively, thus impairing the vasodilator effects of insulin mediated by the IRS-1/PI 3-kinase/Akt/eNOS pathway.
J Clin Endocrinol Metab. 2004 Jun;89(6):2690-6.
Angiotensin II-induced effects on adipose and skeletal muscle tissue blood flow and lipolysis in normal-weight and obese subjects.
Goossens GH, Blaak EE, Saris WH, van Baak MA.
Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands.
The present study was designed to investigate the effects of angiotensin II (Ang II) on adipose and skeletal muscle tissue blood flow and lipolysis in normal-weight and obese subjects using the microdialysis technique. Microdialysis probes were placed in the abdominal sc adipose tissue left and right from the umbilicus and in the gastrocnemius muscle of both legs in eight normal-weight and eight obese men. Probes were consecutively perfused with 1.0 nM Ang II, 1.0 microM Ang II, and 1.0 microM Ang II + 48 microM hydralazine or with Ringer solution (control). Ethanol and glycerol concentrations in the dialysate were measured as an indicator of local blood flow and lipolysis, respectively. Ang II caused an increase in ethanol outflow/inflow ratio, compared with baseline values both in adipose tissue (average of both groups, Ang 1.0 nM: 0.03 +/- 0.01, P = 0.02; Ang 1.0 microM: 0.05 +/- 0.01, P < 0.01) and muscle (average of both groups, Ang 1.0 nM: 0.02 +/- 0.01, P = 0.09; Ang 1.0 microM: 0.04 +/- 0.01, P = 0.01), indicating a decrease in local blood flow. These effects were not significantly different in obese and normal-weight subjects. The decrease in local blood flow was accompanied by unchanged interstitial glycerol concentrations in adipose tissue (except during the supraphysiological dose) and skeletal muscle, suggesting that Ang II inhibits lipolysis in both tissues. Thus, the present data suggest that Ang II decreases local blood flow in a dose-dependent manner and inhibits lipolysis both in adipose and skeletal muscle tissue. These effects were not significantly different in obese and normal-weight subjects in both tissues.
dr frankenstein
Topic starter
28/07/2019 11:46 pm
for natural bodybuilders (no roids).
inhibits Testosterone production.
J Biol Chem. 1988 Apr 15;263(11):5070-4.
Angiotensin II receptors and inhibitory actions in Leydig cells.
Khanum A, Dufau ML.
dr frankenstein
Topic starter
29/07/2019 12:09 am
Endocrinology. 2006 Dec;147(12):6046-55.
Angiotensin II-mediated protein kinase D activation stimulates aldosterone and cortisol secretion in H295R human adrenocortical cells.
Romero DG, Welsh BL, Gomez-Sanchez EP, Yanes LL, Rilli S, Gomez-Sanchez CE.
Division of Endocrinology, Department of Medicine, Montgomery Veterans Affairs Medical Center, and The University of Mississippi Medical Center, 2500 North State Street, Jackson, Mississippi 39216, USA.
Protein kinases are important mediators in intracellular signaling. Angiotensin II is the most important modulator of adrenal zona glomerulosa cell physiology. Angiotensin II regulates steroidogenesis and proliferation among many other metabolic processes. H295R human adrenal cells are a widely used experimental model to study adrenal cell physiology and metabolism. We screened for protein kinase expression levels using the Kinetwork system in H295R cells after 3 h angiotensin II treatment. Protein kinase D (PKD) was the protein kinase that suffers the most dramatic changes. PKD is a member of a new class of serine/threonine protein kinases that is activated by phosphorylation. Our studies indicated that angiotensin II time- and dose-dependently increased PKD phosphorylation, which occurred within 2 min of angiotensin II treatment and at concentrations as low as 1 nm. PKD phosphorylation was also dose-dependently increased by the PKC activator phorbol 12-myristate 13-acetate. Angiotensin II-mediated PKD phosphorylation was blocked by several PKC inhibitors. Furthermore, PKCepsilon translocation inhibitor peptide decreased angiotensin II-mediated PKD phosphorylation, and PKCepsilon down-regulation by RNA interference also decreased PKD phosphorylation mediated by angiotensin II. Cotransfection of constitutively active PKD mutant constructs up-regulated aldosterone synthase and 11beta-hydroxylase expression in reporter assays. Constitutively active PKD mutants increased aldosterone and cortisol secretion under angiotensin II stimulatory conditions. This study reveals that PKD is an intracellular signaling mediator of angiotensin II regulation of steroidogenesis in human adrenal cells. These data provide new insights into the molecular mechanisms involved in angiotensin II-induced physiological and pathophysiological events in adrenal cells.
Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2271-6.
Angiotensin II-induced protein kinase D activation is regulated by protein kinase Cdelta and mediated via the angiotensin II type 1 receptor in vascular smooth muscle cells.
Tan M, Xu X, Ohba M, Cui MZ.
Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
OBJECTIVE: Angiotensin II (Ang II), through its specific signaling cascades, exerts multiple effects on vascular smooth muscle cells (SMCs). It has been shown that Ang II stimulates activation of protein kinase D (PKD), a member of a new class of serine-threonine kinases. However, little is known regarding the upstream cascade of the intracellular signaling that leads to PKD activation. In the present study, we investigated upstream molecules that mediate Ang II-induced PKD activation in SMCs. METHODS AND RESULTS: Protein kinase C (PKC) inhibitors completely block Ang II-induced PKD activation, and pretreatment with phorbol 12,13-dibutyrate downregulates Ang II-induced PKD activation, indicating that classical or novel isoforms of PKC mediate Ang II-induced PKD activation. Furthermore, the finding that rottlerin, a PKCdelta-specific inhibitor, blocks PKD activation suggests that PKCdelta, a member of novel PKCs, mediates Ang II-induced PKD activation. By using dominant-negative approaches, our results demonstrate that expression of the dominant-negative PKCdelta, but neither the dominant-negative form of PKCepsilon nor PKCzeta, inhibits PKD activation. These results further substantiate the finding that Ang II-induced PKD activation is mediated by PKCdelta. Moreover, using selective Ang II receptor antagonists, our data show that the Ang II type 1 (AT1) receptor but not the AT2 mediates Ang II-stimulated PKD activation. CONCLUSIONS: This study reveals for the first time that Ang II-induced PKD activation is mediated via AT1 and regulated by PKCdelta in living cells. These data may provide new insights into molecular mechanisms involved in Ang II-induced physiological and pathological events.
J Biol Chem. 2005 Sep 2;280(35):30814-28.
Angiotensin II inhibits bTREK-1 K+ channels in adrenocortical cells by separate Ca2+- and ATP hydrolysis-dependent mechanisms.
Enyeart JJ, Danthi SJ, Liu H, Enyeart JA.
Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210-1239, USA.
Bovine adrenocortical cells express bTREK-1 K+ channels that set the resting membrane potential (V(m)) and couple angiotensin II (AngII) and adrenocorticotropic hormone (ACTH) receptors to membrane depolarization and corticosteroid secretion. In this study, it was discovered that AngII inhibits bTREK-1 by separate Ca2+- and ATP hydrolysis-dependent signaling pathways. When whole cell patch clamp recordings were made with pipette solutions that support activation of both Ca2+- and ATP-dependent pathways, AngII was significantly more potent and effective at inhibiting bTREK-1 and depolarizing adrenal zona fasciculata cells, than when either pathway is activated separately. External ATP also inhibited bTREK-1 through these two pathways, but ACTH displayed no Ca2+-dependent inhibition. AngII-mediated inhibition of bTREK-1 through the novel Ca2+-dependent pathway was blocked by the AT1 receptor antagonist losartan, or by including guanosine-5'-O-(2-thiodiphosphate) in the pipette solution. The Ca2+-dependent inhibition of bTREK-1 by AngII was blunted in the absence of external Ca2+ or by including the phospholipase C antagonist U73122, the inositol 1,4,5-trisphosphate receptor antagonist 2-amino-ethoxydiphenyl borate, or a calmodulin inhibitory peptide in the pipette solution. The activity of unitary bTREK-1 channels in inside-out patches from adrenal zona fasciculata cells was inhibited by application of Ca2+ (5 or 10 microM) to the cytoplasmic membrane surface. The Ca2+ ionophore ionomycin also inhibited bTREK-1 currents through channels expressed in CHO-K1 cells. These results demonstrate that AngII and selected paracrine factors that act through phospholipase C inhibit bTREK-1 in adrenocortical cells through simultaneous activation of separate Ca2+- and ATP hydrolysis-dependent signaling pathways, providing for efficient membrane depolarization. The novel Ca2+-dependent pathway is distinctive in its lack of ATP dependence, and is clearly different from the calmodulin kinase-dependent mechanism by which AngII modulates T-type Ca2+ channels in these cells.
dr frankenstein
Topic starter
29/07/2019 12:27 am
Atherosclerosis. 2006 Nov 14.
Angiotensin II induces IL-6 expression and the Jak-STAt3 pathway in aortic adventitia of LDL receptor-deficient mice.
Recinos A 3rd, Lejeune WS, Sun H, Lee CY, Tieu BC, Lu M, Hou T, Boldogh I, Tilton RG, Brasier AR.
Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
Angiotensin II (A-II), the major effector peptide of the renin angiotensin system potently accelerates progression of atherosclerosis. To investigate its effects on vascular inflammatory mechanisms, we elucidated vascular cytokine expression during early lesion development in A-II-infused atherosclerosis-prone LDLR(-/-) mice. Male LDLR(-/-) mice were placed on a "Western" high-fat diet for 4 weeks, followed by sham or A-II infusion for 7 weeks. Equal blood pressures and elevations in serum lipids were seen in both groups. Mice were sacrificed when significant A-II-induced plaque development was first detectable, aortae were explanted and culture media assayed for secreted cytokines. Nine cytokines were significantly induced with interleukin-6 (IL-6) being the most highly secreted. Local IL-6 production was confirmed by in situ mRNA hybridization and immunostaining, where the most abundant IL-6 was found in the aortic adventitia, with lesser production by the medial and intimal layers. Immunofluorescence colocalization showed IL-6 expression by fibroblasts and activated macrophages. Activation of downstream IL-6 signaling mediated by the Jak-STAT3 pathway was demonstrated by inducible phospho-Tyr(705)-STAT3 formation in the adventitia and endothelium (of IL-6(+/+)mice only). These findings define cytokine profiles in the A-II infusion model and demonstrate that IL-6, produced by activated macrophages and fibroblasts in the adventitia, induces the Jak-STAT3 pathway during early A-II-induced atherosclerosis.
Horm Res. 2007;67 Suppl 1:64-70.
How proinflammatory cytokines may impair growth and cause muscle wasting.
Thissen JP.
Background: Cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, that are released in response to injury are thought to inhibit growth and cause muscle wasting, at least in part by inhibiting anabolic hormones such as insulin-like growth factor I (IGF-I). Because critical illness in humans is accompanied by high circulating concentrations of growth hormone (GH), which is the main stimulus for IGF-I production by the liver, resistance to GH is thought to contribute to the IGF-I decline observed in catabolic diseases. While TNF-alpha seems to cause GH resistance mainly through downregulation of liver GH receptor expression, IL-6 may inhibit the GH-stimulated Janus kinase and signal transducer and activator of transcription pathways by induction of suppressors of cytokine signaling proteins. Elevations in circulating IGF binding protein-1 levels, as observed in many catabolic situations, may play a role in the decline in muscle mass by decreasing the rate of protein synthesis in skeletal muscle. Furthermore, the increase in local muscle cytokines produced during inflammation makes the muscle GH-resistant and reduces its own IGF-I production. Finally, not only decreased IGF-I production by muscle, but also decreased muscle sensitivity to the anabolic effects of IGF-I, may contribute to muscle wasting observed in response to severe stress. Conclusions: Taken together, proinflammatory cytokines may contribute to the growth retardation and muscle wasting that occur after injury by impairing the GH/IGF-I axis at several levels.
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Angiotensin II induces IL-6 expression.
dr frankenstein
Topic starter
29/07/2019 12:49 am
Nature Med. 2007 Feb;13(2):204-10.
Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states.
Cohn RD, van Erp C, Habashi JP, Soleimani AA, Klein EC, Lisi MT, Gamradt M, ap Rhys CM, Holm TM, Loeys BL, Ramirez F, Judge DP, Ward CW, Dietz HC.
McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland 21205, USA.
Skeletal muscle has the ability to achieve rapid repair in response to injury or disease. Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise. Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-beta (refs. 2,3). TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown. Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1-deficient mice. Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy.
dr frankenstein
Topic starter
29/07/2019 1:11 am
Cell Signal. 2007 Feb 21.
Mechanism of attenuation of angiotensin-II-induced protein degradation by insulin-like growth factor-I (IGF-I).
Russell ST, Eley H, Tisdale MJ.
Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
Insulin-like growth factor-I (IGF-I) has been shown to attenuate protein degradation in murine myotubes induced by angiotensin II through downregulation of the ubiquitin-proteasome pathway, although the mechanism is not known. Angiotensin II is known to upregulate this pathway through a cellular signalling mechanism involving release of arachidonic acid, activation of protein kinase Calpha (PKCalpha), degradation of inhibitor-kappaB (I-kappaB) and nuclear migration of nuclear factor-kappaB (NF-kappaB), and all of these events were attenuated by IGF-I (13.2 nM). Induction of the ubiquitin-proteasome pathway has been linked to activation of the RNA-activated protein kinase (PKR), since an inhibitor of PKR attenuated proteasome expression and activity in response to angiotensin II and prevented the decrease in the myofibrillar protein myosin. Angiotensin II induced phosphorylation of PKR and of the eukaryotic initiation factor-2 (eIF2) on the alpha-subunit, and this was attenuated by IGF-I, by induction of the expression of protein phosphatase 1, which dephosphorylates PKR. Release of arachidonic acid and activation of PKCalpha by angiotensin II were attenuated by an inhibitor of PKR and IGF-I, and the effect was reversed by Salubrinal (15 muM), an inhibitor of eIF2alpha dephosphorylation, as was activation of PKCalpha. In addition myotubes transfected with a dominant-negative PKR (PKRDelta6) showed no release of arachidonate in response to Ang II, and no activation of PKCalpha. These results suggest that phosphorylation of PKR by angiotensin II was responsible for the activation of the PLA(2)/PKC pathway leading to activation of NF-kappaB and that IGF-I attenuates protein degradation due to an inhibitory effect on activation of PKR.
dr frankenstein
Topic starter
29/07/2019 1:34 am
and prolactin implicated?
Am J Physiol. 1994 Feb;266(2 Pt 1):E274-8.
Effects of LHRH and ANG II on prolactin stimulation are mediated by hypophysial AT1 receptor subtype.
Becu-Villalobos D, Lacau-Mengido IM, Thyssen SM, Diaz-Torga GS, Libertun C.
Laboratorio de Neuroendocrinologia, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires, Argentina.
Endocrinology. 1982 Oct;111(4):1045-50.
Angiotensin II receptors and prolactin release in pituitary lactotrophs.
Aguilera G, Hyde CL, Catt KJ.
--------------------------
excess ang II, never!
dr frankenstein
29/07/2019 1:52 am
for natural bodybuilders (no roids).
inhibits testosterone production.
J Biol Chem. 1988 Apr 15;263(11):5070-4.
Angiotensin II receptors and inhibitory actions in Leydig cells.
Khanum A, Dufau ML.
29/07/2019 2:21 am
for natural bodybuilders (no roids).
inhibits testosterone production.
J Biol Chem. 1988 Apr 15;263(11):5070-4.
Angiotensin II receptors and inhibitory actions in Leydig cells.
Khanum A, Dufau ML.
"The medals don't mean anything and the glory doesn't last. It's all about your happiness. The rewards are going to come, but my happiness is just loving the sport and having fun performing" ~ Jackie Joyner Kersee.
29/07/2019 2:51 am
Good job Thank God for ACE inhibitors.
Seabiscuit Hogg is a fictious internet character. It is not recommended that you receive medical advice from fictious internet characters.
SBH :)
29/07/2019 3:18 am
can you spell micardis?
jb
29/07/2019 3:36 am
Diovan's not bad either. My prescription plan wouldn't pay for an angiotenson 2 blocker. Had to go with the ACE inhibitor for my BP.
Seabiscuit Hogg is a fictious internet character. It is not recommended that you receive medical advice from fictious internet characters.
SBH :)
Topic starter
29/07/2019 4:04 am
estrogen upregulate ANG II, subsequently cortisol is increased by ANG II.
J Hypertens. 1992 Apr;10(4):361-6.
Regulation of angiotensinogen gene expression by estrogen.
Gordon MS, Chin WW, Shupnik MA.
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
OBJECTIVE: Clarification of the role of estrogen in the regulation of angiotensinogen gene expression in multiple tissues. DESIGN: The effect of 17 beta-estradiol (E2; 10 micrograms/100 mg body weight) administration in ovariectomized (OVX) rats upon angiotensinogen messenger RNA (mRNA) levels in multiple tissues was assessed. Confounding ovarian factors were thus removed by studying the animals in the castrate state. Controls consisted of OVX and intact female rats. METHODS: Adult female Sprague-Dawley rats were ovariectomized and experiments begun 21 days postsurgery. Animals were injected with E2 and studied after 0, 1, 4, and 24 h of treatment. Levels of angiotensinogen mRNA were determined by Northern blot analysis using beta-actin mRNA as an internal standard. RESULTS: A single angiotensinogen mRNA species with molecular size of approximately 1800 bp was observed in rat liver, aorta, kidney, cardiac atria, hypothalamus and whole brain. Little or no angiotensinogen mRNA was identified in the pituitary gland. Angiotensinogen mRNA was most abundant in rat liver, hypothalamus, aorta and progressively less abundant in whole brain, cardiac atria and kidney. A twofold induction of hepatic angiotensinogen mRNA levels in E2-OVX rats was observed by 4h. The angiotensinogen mRNA levels in kidney were threefold higher by 4 h compared with OVX control animals. In aorta, the angiotensinogen mRNA level was also threefold higher by 1 h after E2 treatment. No significant effect of estradiol treatment was observed in cardiac atria although the level of angiotensinogen mRNA was higher in intact female rats compared with OVX controls. CONCLUSION: These results suggest that estrogen modulates angiotensinogen gene expression in a tissue-specific manner.
Am J Physiol. 1992 Aug;263(2 Pt 1):E355-61.
Stimulation of angiotensinogen mRNA levels in rat pituitary by estradiol.
Healy DP, Ye MQ, Yuan LX, Schachter BS.
Department of Pharmacology, Mount Sinai School of Medicine, City University of New York, New York 10029.
Angiotensin II (ANG II) is a putative paracrine hormone in the anterior pituitary. Angiotensinogen mRNA, however, is not detectable by Northern blot hybridization, suggesting that ANG II may not be synthesized within the pituitary. An alternative explanation may be that angiotensinogen gene activity is low under normal conditions, with angiotensinogen mRNA being below the level of detection. Utilizing a sensitive solution hybridization method, we sought to determine whether angiotensinogen mRNA could be detected in pituitaries from normal male rats or ovariectomized (OVX) rats treated with estradiol (E2) for 4 days. Very low levels of angiotensinogen mRNA were detected from male or OVX rat pituitaries, but E2 treatment resulted in a marked dose-dependent increase in pituitary angiotensinogen mRNA levels. Levels of angiotensinogen within the pituitary were not significantly different after the E2 treatment. Angiotensinogen mRNA levels in liver and brain were much higher than in the pituitary but were not altered significantly by the chronic E2 treatment. These results are consistent with the local synthesis of angiotensinogen in the pituitary and further suggest that pituitary angiotensinogen gene transcription is regulated by estrogen.
J Steroid Biochem Mol Biol. 1994 Feb;48(2-3):207-14.
Estrogen action on hepatic synthesis of angiotensinogen and IGF-I: direct and indirect estrogen effects.
Krattenmacher R, Knauthe R, Parczyk K, Walker A, Hilgenfeldt U, Fritzemeier KH.
Schering AG, Berlin, Germany.
In the present study effects of estrogens (natural estradiol and synthetic ethinyl estradiol) on liver derived proteins (angiotensinogen, IGF-I) were investigated in vivo in ovariectomized rats and in vitro in a rat hepatoma cell line (Fe33). The aim of this study was to establish both an animal and an in vitro model for quantification of the hepatic activity of given estrogenic compounds, and to study underlying mechanisms as regards the question of direct or indirect mode of estrogen action. In ovariectomized rats subcutaneous (s.c.)-treatment for 11 days with either estradiol (E2) or ethinyl estradiol (EE) (dose range 0.1-3 micrograms/animal/day) induced a comparable dose-dependent increase in uterine weight indicating a similar estrogenic potency of the two estrogens. Equipotency was also found as regards the effects on IGF-I plasma levels which dose-dependently decreased by about 50% at the highest dose tested (3 micrograms/animal/day). The decrease in IGF-I serum levels was accompanied by a significant 40% decrease in liver IGF-I mRNA. In contrast angiotensinogen plasma levels were affected only by EE (60% increase for the 3 micrograms/animal/day dose) but not by E2. When rats, in addition to ovariectomy, were also hypophysectomized (substituted with human growth hormone and dexamethasone) angiotensinogen again increased by 80% upon administration of 3 micrograms/animal/day EE, whereas IGF-I remained unaffected by EE. In a rat hepatoma cell line (Fe33) which is stably transfected with an estrogen receptor expression plasmid, 10 nmol/l EE for 24 h caused a 2.4-fold increase in angiotensinogen mRNA level. We conclude from our studies that estrogen effects on angiotensinogen serum levels in the rat are direct effects via the hepatic estrogen receptor, whereas estrogen effects on IGF-I serum levels are indirect effects, the primary target of estrogen action being probably the pituitary. The changes in angiotensinogen serum levels in the rat model are comparable to the situation in humans indicating the rat model and the Fe33 model to be useful tools to study the hepatic activity of estrogenic compounds.
Regul Pept. 2005 Jan 15;124(1-3):7-17.
Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat.
Baiardi G, Macova M, Armando I, Ando H, Tyurmin D, Saavedra JM.
Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, MSC 1514, Building 10, Room 2D-57, Bethesda, MD 20892, USA.
We studied renal AT1 and AT2 receptors in male, female, ovariectomized and ovariectomized-estrogen-treated Wistar-Hanover and Wistar-Kyoto rats. AT1 receptors and AT1A receptor mRNA predominated, with no significant differences between males and females. AT2 receptor expression was restricted in female rats to the capsule, the transition zone between outer and inner medulla, the endothelium lining the papilla, and arcuate arteries and veins. There were no AT2 receptors in male rats, while male mice express substantial numbers of estrogen-dependent AT2 receptors. Arcuate arteries and veins expressed AT1B mRNA in males and females, and AT2 mRNA in females only. AT1 receptor and AT2 receptor expression were estrogen-dependent, with increases in AT1 and AT2 receptor expression after estrogen treatment in ovariectomized rats. Estrogen treatment increased prostaglandin E2 (PGE2) and cGMP concentrations in the renal medulla, and eNOS expression in cortical arteries. In rodents, expression of renal Angiotensin II receptor types is estrogen-dependent, with significant species, strain and area differences. Our results support an important role for AT2 receptors in the regulation of renal function and in the protective effects of estrogen in the kidney.
Mol Cell Endocrinol. 1989 Jun;64(1):45-53.
Angiotensin II-stimulated cortisol secretion is mediated by a hormone-sensitive phospholipase C in bovine adrenal fasciculata/reticularis cells.
Bird IM, Meikle I, Williams BC, Walker SW.
University Department of Biochemistry, Edinburgh, Scotland, U.K.
Conditions have been established for the incorporation of [3H]inositol ([3H]Ins) into the phosphoinositides of cultured bovine adrenal zona fasciculata/reticularis (ZFR) cells. Stimulation of these prelabelled cells with angiotensin II (10(-11)-10(-7) M AII) resulted in the dose-dependent (max. 16-fold at 10(-7) M AII), time-dependent formation of water-soluble radiolabelled products which show the same chemical and chromatographic properties as [3H]InsP, [3H]InsP2 and [3H]InsP3 standards. The results of the time-course studies of the changes in these products are consistent with the view that AII rapidly (less than 15 s) induces the activation of a polyphosphoinositide-specific phospholipase C. The action of this phospholipase on the polyphosphoinositides is sustained throughout 15 min of stimulation. The dose dependency of this response correlates closely with cortisol output and is reduced (to 52%, P less than 0.00005), but not abolished, in the absence of extracellular Ca2+. To our knowledge these results are the first clear demonstration that AII stimulates a polyphosphoinositide-specific phospholipase C in bovine ZFR cells.
Endocrinology. 1993 May;132(5):2206-12.
Angiotensin II stimulates growth and steroidogenesis in zona fasciculata/reticularis cells from bovine adrenal cortex via the AT1 receptor subtype.
Clyne CD, Nicol MR, MacDonald S, Williams BC, Walker SW.
Edinburgh University, Department of Pharmacology, United Kingdom.
Primary cultures of bovine adrenocortical zona fasciculata/reticularis (zfr) cells responded to angiotensin II (AII) with a dose-dependent increase in [3H]thymidine incorporation into DNA. The effect was maximal at 100 nmol/liter AII, and was dose dependently inhibited by (sar1, ala8)-AII (saralasin) and DuP753, but not by PD123177. Both AII-stimulated cortisol secretion and phosphoinositidase C activity were also inhibited by saralasin and DuP753, but not by PD123177. Pharmacological analysis of the antagonism of AII-stimulated cortisol secretion by saralasin and DuP753 produced pA2 values of 8.79 and 7.02, respectively. Whereas the pA2 for saralasin agreed closely with previous measurements in other systems, DuP753 was at least one order of magnitude less potent in inhibiting the action of AII in bovine zfr cells compared to previous measurements in rabbit vascular smooth muscle. We conclude that the steroidogenic and mitogenic effects of AII in bovine zfr cells are mediated by the AT1 receptor.
dr frankenstein
Topic starter
29/07/2019 4:24 am
at glomerulosa cells; aldosterone.
Mol Cell Endocrinol. 2007 Jul 15;273(1-2):1-5.
The growth-promoting effects of angiotensin II in adrenal glomerulosa cells: An interactive tale.
Otis M, Campbell S, Payet MD, Gallo-Payet N.
Service of Endocrinology, Faculty of Medicine, Universit� de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4.
The zona glomerulosa of the adrenal cortex is well-known for its high level of proliferation, compared to the adjacent zona fasciculata, both in in vivo and in vitro conditions. Angiotensin II (Ang II) is a potent growth factor for glomerulosa cells, appearing as a proliferative factor in vivo, under sodium-deficient diet conditions, as well as in vitro, in studies conducted with whole zona glomerulosa. However, in cells maintained in primary culture for 3 days, Ang II rather promotes cellular hypertrophy with a concomitant arrest in basal cell proliferation. The present essay aims at providing experimental arguments supporting such unexpected observations, with particular focus on the modulatory impact of the extracellular environment on Ang II action, namely AT(1) receptor-induced signaling pathways and cell responses.
Endocrinology. 2007 Feb;148(2):585-93.
Characterization and phospholipase D mediation of the angiotensin II priming response in adrenal glomerulosa cells.
Bollag WB, Kent P, White S, Malinova M, Isales CM, Calle RA.
Program in Regenerative Medicine, Department of Medicine, Institute of Molecular Medicine and Genetics, 1120 15th Street, Medical College of Georgia, Augusta, Georgia 30912-2630, USA.
Bovine adrenal glomerulosa cells are primed by an initial treatment with angiotensin II (AngII) to respond with enhanced secretion to a second exposure to AngII or agents that increase calcium influx. We hypothesized that the mechanism of priming involves a persistent increase in diacylglycerol (DAG) generated via sustained activity of phospholipase D (PLD). In this report, we sought to define the time frame of this priming response as well as determine its mechanism using assays of aldosterone secretion, PLD activation, and radiolabeled diacylglycerol levels. We found that in primary cultures priming was observed for up to 50 min after AngII washout, suggesting that the priming window is protracted in these cultures relative to freshly isolated cells. The phorbol ester, phorbol 12,13-dibutyrate (PDBu), was used to investigate the role of sustained PLD activation in the persistent DAG and priming responses. PDBu was able to both prime glomerulosa cells to respond with enhanced secretion to AngII and elicit a persistent increase in DAG after PDBu washout. This persistent increase in DAG levels with an initial exposure to PDBu or AngII was not the result of maintained PLD activity after agent removal because PLD activation returned to basal levels by 30 min after washout. Finally, inhibition of PLD signaling during the initial AngII treatment inhibited the subsequent response to AngII or another agent that increases calcium influx. Thus, our results suggest that persistent DAG resulting from PLD signaling mediates the priming response to AngII or PDBu.
Endocrinology. 1990 Sep;127(3):1436-43.
A potential role for phospholipase-D in the angiotensin-II-induced stimulation of aldosterone secretion from bovine adrenal glomerulosa cells.
Bollag WB, Barrett PQ, Isales CM, Liscovitch M, Rasmussen H.
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510.
The mechanism by which angiotensin-II (Ang II) stimulates aldosterone secretion from adrenal glomerulosa cells involves a phospholipase-C-mediated increase in phosphoinositide turnover and diacylglycerol (DAG) production. Because agonist-induced activation of phospholipase-D (PLD) also contributes to elevations in DAG in other cell types, the ability of Ang II to stimulate PLD activity in cultured bovine adrenal glomerulosa cells was examined. Ang II elicited significant increases in the levels of phosphatidic acid and, in the presence of ethanol, of phosphatidylethanol, a more specific marker for PLD activation. The potential role of this increased PLD activity in the regulation of aldosterone secretion was examined by investigating the ability of exogenous PLD to alter secretory rates. PLD alone dose-dependently increased aldosterone secretion from 5.9 +/- 0.5 to 135 +/- 48 pg/min.mg protein. In the presence of the calcium channel agonist Bay K 8644, which by itself had only a modest effect on aldosterone production, the stimulatory action of PLD was enhanced, yielding a secretory rate (442 +/- 119 pg/min.mg protein) that was approximately 60% of that elicited by 10 nM Ang II (763 +/- 182 pg/min.mg protein). Exogenous PLD also induced a significant increase in DAG levels (from 0.76 +/- 0.03 to 1.10 +/- 0.1 nmol/mg protein), which was not altered by the addition of Bay K 8644. However, PLD did not stimulate inositol phosphate production. These data indicate that 1) Ang II activates PLD; 2) exogenous PLD can elevate aldosterone secretory rates and DAG levels without eliciting phosphoinositide hydrolysis; and 3) the stimulatory action of exogenous PLD on aldosterone secretion is enhanced in the presence of Bay K 8644. Thus, PLD-induced DAG production may play an important role in the Ang II-mediated stimulation of aldosterone secretion from the adrenal zona glomerulosa.
J Endocrinol. 2007 Aug;194(2):429-40.
Regulators of G-protein signaling 4 in adrenal gland: localization, regulation, and role in aldosterone secretion.
Romero DG, Zhou MY, Yanes LL, Plonczynski MW, Washington TR, Gomez-Sanchez CE, Gomez-Sanchez EP.
Division of Endocrinology, G V (Sonny) Montgomery VA Medical Center.
Regulators of G-protein signaling (RGS proteins) interact with Galpha subunits of heterotrimeric G-proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G-protein-coupled receptor (GPCR)-ligand interaction. Angiotensin II (Ang II) interacts with its GPCR in adrenal zona glomerulosa cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. On screening for adrenal zona glomerulosa-specific genes, we found that RGS4 was exclusively localized in the zona glomerulosa of the rat adrenal cortex. We studied RGS4 expression and regulation in the rat adrenal gland, including the signaling pathways involved, as well as the role of RGS4 in steroidogenesis in human adrenocortical H295R cells. We reported that RGS4 mRNA expression in the rat adrenal gland was restricted to the adrenal zonal glomerulosa and upregulated by low-salt diet and Ang II infusion in rat adrenal glands in vivo. In H295R cells, Ang II caused a rapid and transient increase in RGS4 mRNA levels mediated by the calcium/calmodulin/calmodulin-dependent protein kinase and protein kinase C pathways. RGS4 overexpression by retroviral infection in H295R cells decreased Ang II-stimulated aldosterone secretion. In reporter assays, RGS4 decreased Ang II-mediated aldosterone synthase upregulation. In summary, RGS4 is an adrenal gland zona glomerulosa-specific gene that is upregulated by aldosterone secretagogues, in vivo and in vitro, and functions as a negative feedback of Ang II-triggered intracellular signaling. Alterations in RGS4 expression levels or functions may be involved in deregulations of Ang II signaling and abnormal aldosterone secretion.
Endocrinology. 2006 Aug;147(8):3889-97.
RGS2 is regulated by angiotensin II and functions as a negative feedback of aldosterone production in H295R human adrenocortical cells.
Romero DG, Plonczynski MW, Gomez-Sanchez EP, Yanes LL, Gomez-Sanchez CE.
Division of Endocrinology, Montgomery Veterans Administration Medical Center, USA.
Regulator of G protein signaling (RGS) proteins interact with Galpha-subunits of heterotrimeric G proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G protein-coupled receptor-ligand interaction. Angiotensin (Ang) II interacts with its G protein-coupled receptor in zona glomerulosa adrenal cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. We studied Ang II-mediated regulation of RGS2, the role of RGS2 in steroidogenesis, and the intracellular signal events involved in H295R human adrenal cells. We report that both H295R cells and human adrenal gland express RGS2 mRNA. In H295R cells, Ang II caused a rapid and transient increase in RGS2 mRNA levels quantified by real-time RT-PCR. Ang II effects were mimicked by calcium ionophore A23187 and blocked by calcium channel blocker nifedipine. Ang II effects also were blocked by calmodulin antagonists (W-7 and calmidazolium) and calcium/calmodulin-dependent kinase antagonist KN-93. RGS2 overexpression by retroviral infection in H295R cells caused a decrease in Ang II-stimulated aldosterone secretion but did not modify cortisol secretion. In reporter assays, RGS2 decreased Ang II-mediated aldosterone synthase up-regulation. These results suggest that Ang II up-regulates RGS2 mRNA by the calcium/calmodulin-dependent kinase pathway in H295R cells. RGS2 overexpression specifically decreases aldosterone secretion through a decrease in Ang II-mediated aldosterone synthase-induced expression. In conclusion, RGS2 expression is induced by Ang II to terminate the intracellular signaling cascade generated by Ang II. RGS2 alterations in expression levels or functionality could be implicated in deregulations of Ang II signaling and abnormal aldosterone secretion by the adrenal gland.
Endocrinology. 2007 Jun;148(6):2644-52.
Disabled-2 is expressed in adrenal zona glomerulosa and is involved in aldosterone secretion.
Romero DG, Yanes LL, de Rodriguez AF, Plonczynski MW, Welsh BL, Reckelhoff JF, Gomez-Sanchez EP, Gomez-Sanchez CE.
Division of Endocrinology, Department of Medicine, Montgomery VA Medical Center and The University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
The differentiation of the adrenal cortex into functionally specific zones is probably due to differential temporal gene expression during fetal growth, development, and adulthood. In our search for adrenal zona glomerulosa-specific genes, we found that Disabled-2 (Dab2) is expressed in the zona glomerulosa of the rat adrenal gland using a combination of laser capture microdissection, mRNA amplification, cDNA microarray hybridization, and real-time RT-PCR. Dab2 is an alternative spliced mitogen-regulated phosphoprotein with features of an adaptor protein and functions in signal transduction, endocytosis, and tissue morphogenesis during embryonic development. We performed further studies to analyze adrenal Dab2 localization, regulation, and role in aldosterone secretion. We found that Dab2 is expressed in the zona glomerulosa and zona intermedia of the rat adrenal cortex. Low-salt diet treatment increased Dab2-long isoform expression at the mRNA and protein level in the rat adrenal gland, whereas high-salt diet treatment did not cause any significant modification. Angiotensin II infusion caused a transient increase in both Dab2 isoform mRNAs in the rat adrenal gland. Dab2 overexpression in H295R human adrenocortical cells caused an increase in aldosterone synthase expression and up-regulated aldosterone secretion under angiotensin II-stimulated conditions. In conclusion, Dab2 is an adrenal gland zona glomerulosa- and intermedia-expressed gene that is regulated by aldosterone secretagogues such as low-salt diet or angiotensin II and is involved in aldosterone synthase expression and aldosterone secretion. Dab2 may therefore be a modulator of aldosterone secretion and be involved in mineralocorticoid secretion abnormalities.
dr frankenstein