17β-Estradiol attenuates p38MAPK activity but not PKCα induced by angiotensin II in the brain

in Journal of Endocrinology
Correspondence should be addressed to G Almeida-Pereira: g.almeidapereira@gmail.com
Restricted access

17β-Estradiol (E2) has been shown to modulate the renin–angiotensin system in hydromineral and blood pressure homeostasis mainly by attenuating angiotensin II (ANGII) actions. However, the cellular mechanisms of the interaction between E2 and angiotensin II (ANGII) and its physiological role are largely unknown. The present experiments were performed to better understand the interaction between ANGII and E2 in body fluid control in female ovariectomized (OVX) rats. The present results are the first to demonstrate that PKC/p38 MAPK signaling is involved in ANGII-induced water and sodium intake and oxytocin (OT) secretion in OVX rats. In addition, previous data from our group revealed that the ANGII-induced vasopressin (AVP) secretion requires ERK1/2 signaling. Therefore, taken together, the present observations support a novel concept that distinct intracellular ANGII signaling gives rise to distinct neurohypophyseal hormone release. Furthermore, the results show that E2 attenuates p38 MAPK phosphorylation in response to ANGII but not PKC activity in the hypothalamus and the lamina terminalis, suggesting that E2 modulates ANGII effects through the attenuation of the MAPK pathway. In conclusion, this work contributes to the further understanding of the interaction between E2 and ANGII signaling in hydromineral homeostasis, as well as it contributes to further elucidate the physiological relevance of PKC/p38 MAPK signaling on the fluid intake and neurohypophyseal release induced by ANGII.

 

      Society for Endocrinology

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 339 339 137
Full Text Views 69 69 2
PDF Downloads 13 13 0

Altmetrics

Related Articles

Figures

  • View in gallery

    E2 and ANGII interaction in water and sodium intake: role of PKC inhibitor Chelerythrine. Cumulative water intake (A) and water intake at the end of the 60 min test (C), cumulative sodium intake (B) and sodium intake at the end of the 60-min test (D). A subset of animals from both oil- and E2-treated OVX groups received central injection of PKC inhibitor Chelerythrine or vehicle before ANGII or vehicle injection. After ANGII injection the fluids intake were evaluated. Values are adjusted per 100 g of body weight (bw) and expressed as means ± s.e.m. +P < 0.05 vs respective Veh–Veh, #P < 0.05 vs respective Veh–ANGII, *P < 0.05 vs respective oil-treated OVX group. The sample size (n) is indicated in parenthesis.

  • View in gallery

    E2 and ANGII interaction in neurohypophysial hormones release: role of PKC inhibitor Chelerythrine. OT release (A) and AVP release (B) analyses. A subset of animals from both oil- and E2-treated OVX groups received central injection of PKC inhibitor Chelerythrine or vehicle before ANGII or vehicle injection. The blood samples were collected 5 min after ANGII injection. Values are expressed as means ± s.e.m. +P < 0.05 vs respective Veh–Veh, #P < 0.05 vs respective Veh–ANGII, *P < 0.05 vs respective oil-treated OVX group. The sample size (n) is indicated inside the columns.

  • View in gallery

    E2 and ANGII interaction in water and sodium intake: role of p38 MAPK inhibitor SB203580. Cumulative water intake (A) and water intake at the end of the 60 min test (C), cumulative sodium intake (B) and sodium intake at the end of the 60 min test (D). A subset of animals from both oil- and E2-treated OVX groups received central injection of p38 MAPK inhibitor SB203580 or vehicle before ANGII or vehicle injection. After ANGII injection the fluids intake were evaluated. Values are adjusted per 100 g of body weight (bw) and expressed as means ± s.e.m. +P < 0.05 vs respective Veh–Veh, #P < 0.05 vs respective Veh–ANGII, *P < 0.05 vs respective oil-treated OVX group. The sample size (n) is indicated in parenthesis.

  • View in gallery

    E2 and ANGII interaction in neurohypophysial hormones release: role of p38 MAPK inhibitor SB203580. OT release (A) and AVP release (B) analyses. A subset of animals from both oil- and E2-treated OVX groups received central injection of p38 MAPK inhibitor SB203580 or vehicle before ANGII or vehicle injection. The blood samples were collected five minutes after ANGII injection. Values are expressed as means ± s.e.m. +P < 0.05 vs respective Veh–Veh, #P < 0.05 vs respective Veh–ANGII, *P < 0.05 vs respective oil-treated OVX group. The sample size (n) is indicated inside the columns.

  • View in gallery

    Effect of E2 on ANGII-induced PKCα translocation in the lamina terminalis and hypothalamus. PKCα translocation in the lamina terminalis structures (A) and in the PVN and SON (B) analyses. A subset of animals from both oil- and E2-treated OVX groups received central injection of ANGII or vehicle. The brain samples were collected five minutes post injection. Above A: representative blots and corresponding to the groups in the graph below, showing PKCα and paxillin protein levels in the lamina terminalis (MnPO, OVLT and SFO). A: bar graph shows means ± s.e.m. (n = 6–7) of the ratio of C/M PKCα protein expression in the lamina terminalis structures. C refers to the cytosolic fractions and M to the membrane fractions of the lamina terminalis extracts. Above B: representative blots and corresponding to the groups in the graph below, showing PKCα and paxillin protein levels in the hypothalamus (PVN and SON). B: bar graph shows means ± s.e.m. (n = 6–7) of the ratio of C/M PKCα protein expression in the hypothalamus. C refers to the cytosolic fractions and M to the membrane fractions of the hypothalamic extracts. +P < 0.05 vs oil-treated respective group, *P < 0.05 vs OVX–Veh group. The sample size (n) is indicated inside the columns.

  • View in gallery

    Effect of E2 on ANGII-induced p38 MAPK phosphorylation in the lamina terminalis and hypothalamus. p38 MAPK phosphorylation in the PVN and SON (A and B) and in the lamina terminalis structures (C and D) analyses. A subset of animals from both oil- and E2-treated OVX groups received central injection of ANGII or vehicle. The brain samples were collected five minutes post injection. Above A: representative blots and corresponding to the groups in the graph below, showing phosphorylated p38 MAPK, total p38 MAPK and β-actin protein levels in the hypothalamus (PVN and SON). A: bar graph shows means ± s.e.m. of phospho-p38/total p38 protein expression in the hypothalamus. B: bar graph shows means ± s.e.m. of total p38/β-actin protein expression in the hypothalamus. Above C: representative blots and corresponding to the groups in the graph below, showing phosphorylated p38 MAPK, total p38 MAPK and β-actin protein levels in the lamina terminalis (MnPO, OVLT and SFO). C: bar graph shows means ± s.e.m. of phospho-p38/total p38 protein expression in the lamina terminalis. D: bar graph shows means ± s.e.m. of total p38/β-actin protein expression in the lamina terminalis. +P < 0.05 vs oil-treated respective group, *P < 0.05 vs OVX–Veh group. The sample size (n) is indicated inside the columns.

  • View in gallery

    Role of E2 on MKP-1 expression in the lamina terminalis. A subset of animals from both oil- and E2-treated OVX groups received central injection of ANGII or vehicle. The brain samples were collected ten minutes post injection. In the top: representative blots and corresponding to the groups in the graph below, showing MKP-1 and β-actin protein levels in the lamina terminalis (MnPO, OVLT and SFO). At the bottom: bar graph shows means ± s.e.m. of MKP-1/β-actin protein expression in the lamina terminalis. The sample size (n) is indicated inside the columns.

  • View in gallery

    Role of E2 on phospho-p38 MAPK expression in the vasopressinergic magnocellular neurons of the SON in response to ANGII. Representative immunofluorescence photomicrographs of coronal sections showing the AVP and phospho-p38 MAPK staining and their co-localization (merge) in the supraoptic nucleus in response to ANGII stimulation in oil- and E2-treated OVX rats. OC, optic chiasm. Objective is ×40. The scale bar represents 100 µm. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0095.

  • View in gallery

    Role of E2 on phospho-p38 MAPK expression in the oxytocinergic magnocellular neurons on the SON in response to ANGII. Representative immunofluorescence photomicrographs of coronal sections showing the OT and phospho-p38 MAPK staining and their co-localization (merge) in the supraoptic nucleus in response to ANGII stimulation in oil- and E2-treated OVX rats. OC, optic chiasm. Objective is ×40. The scale bar represents 100 µm. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0095.

  • View in gallery

    Role of E2 on PKCα expression in the SFO in response to ANGII. Representative immunofluorescence photomicrographs of coronal sections showing the PKCα protein staining in the subfornical organ in response to ANGII stimulation oil- and E2-treated OVX rats. Objective is ×20. The scale bar represents 100 µm. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0095.

  • View in gallery

    Role of E2 on phospho-p38 MAPK expression in the SFO in response to ANGII. Representative immunofluorescence photomicrographs of coronal sections showing the phospho-p38 MAPK protein staining in the subfornical organ in response to ANGII stimulation oil- and E2-treated OVX rats. Objective is ×20. The scale bar represents 100 µm. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0095.

  • View in gallery

    E2 and ANGII interaction in body fluid control. Schematic summary of the proposed interaction between E2 and ANGII in water and sodium intake (left): E2 modulates fluid intake through attenuation of p38 MAPK phosphorylation and PKC mediated by E2 can be involved in AT1 desensitization in the lamina terminalis. In the middle and right, the proposed interaction between E2 and ANGII in oxytocin (OT) and vasopressin (AVP) release: middle, effect of E2 on ANGII-induced OT release by preventing p38 MAPK phosphorylation within the SFO that represents the major site of action of circulating ANGII on the neurohypophysial hormone release through its angiotensinergic connections to PVN and SON; PKC mediated by E2 could be involved in some phosphatase activation which is responsible by dephosphorylation of ERK1/2 in the SFO; right, direct effect of E2 on ANGII-induced OT release by preventing p38 MAPK phosphorylation in the PVN and SON; E2 requires PKC signaling to modulate AVP release induced by ANGII in the PVN and SON. Legend: continuous arrow indicates stimulation and dashed arrow indicates inhibition/desensitization. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0095.

References

Almeida-PereiraGRoratoRReisLCEliasLLKAntunes-RodriguesJ 2013 The role of estradiol in adrenal insufficiency and its interaction with corticosterone on hydromineral balance. Hormones and Behavior 64 847855. (https://doi.org/10.1016/j.yhbeh.2013.10.009)

Almeida-PereiraGColettiRMecawiASReisLCEliasLLKAntunes-RodriguesJ 2016 Estradiol and angiotensin II crosstalk in hydromineral balance: role of the ERK1/2 and JNK signaling pathways. Neuroscience 322 525538. (https://doi.org/10.1016/j.neuroscience.2016.02.067)

AlvesSELopezVMcEwenBSWeilandNG 1998 Differential colocalization of estrogen receptor beta (ERbeta) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: an immunocytochemical study. PNAS 95 32813286. (https://doi.org/10.1073/pnas.95.6.3281)

Antunes-RodriguesJCovianMR 1963 Hypothalamic control of sodium chloride and water intake. Acta Physiology Latin American 13 94100.

Antunes-RodriguesJde CastroMEliasLLKValençaMMMcCannSM 2004 Neuroendocrine control of body fluid metabolism. Physiological Reviews 84 169208. (https://doi.org/10.1152/physrev.00017.2003)

BeltmanJMcCormickFCookSJ 1996 The selective protein kinase C inhibitor, Ro-31-8220, inhibits mitogen-activated protein kinase phosphatase-1 (MKP-1) expression, induces c-Jun expression, and activates Jun N-terminal kinase. Journal of Biological Chemistry 271 2701827024. (https://doi.org/10.1074/jbc.271.43.27018)

BeresfordMJFitzsimonsJT 1992 Intracerebroventricular angiotensin II-induced thirst and sodium appetite in rat are blocked by the AT1 receptor antagonist, losartan (DuP 753), but not by the AT2 antagonist, CGP 42112B. Experimental Physiology 77 761764. (https://doi.org/10.1113/expphysiol.1992.sp003643)

CauntCJKeyseSM 2012 Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signaling. FEBS Journal 280 489504. (https://doi.org/10.1111/j.1742-4658.2012.08716.x)

CirielloJRoderS 2013 17β-Estradiol alters the response of subfornical organ neurons that project to supraoptic nucleus to plasma angiotensin II and hypernatremia. Brain Research 1526 5464. (https://doi.org/10.1016/j.brainres.2013.06.038)

CobleJPJohnsonRFCassellMDJohnsonAKGrobeJLSigmundCD 2014 Activity of protein kinase C-α within the subfornical organ is necessary for fluid intake in response to brain angiotensin. Hypertension 64 141148. (https://doi.org/10.1161/HYPERTENSIONAHA.114.03461)

CobleJPGrobeJLJohnsonAKSigmundCD 2015 Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ. American Journal of Physiology: Regulatory Integrative and Comparative Physiology 308 R238R249. (https://doi.org/10.1152/ajpregu.00486.2014)

DadamFMCaeiroXECisternasCDMacchioneAFCambiassoMJVivasL 2014 Effect of sex chromosome complement on sodium appetite and Fos-immunoreactivity induced by sodium depletion. American Journal of Physiology: Regulatory Integrative and Comparative Physiology 306 R175R184. (https://doi.org/10.1152/ajpregu.00447.2013)

DanielsDYeeDKFluhartySJ 2007 Angiotensin II receptor signalling. Experimental Physiology 92 523527. (https://doi.org/10.1113/expphysiol.2006.036897)

DanielsDMietlickiEGNowakELFluhartySJ 2009 Angiotensin II stimulates water and NaCl intake through separate cell signalling pathways in rats. Experimental Physiology 94 130137. (https://doi.org/10.1113/expphysiol.2008.044446)

EliasPCLEliasLLKMoreiraAC 1998 Padronização do teste de infusão de salina hipertônica para o diagnóstico de diabetes insípido com dosagem da vasopressina plasmática. Archive Brazilian Endocrinology Metabolism 42 198204.

FergusonAVBainsJS 1996 Electrophysiology of the circumventricular organs. Frontiers in Neuroendocrinology 17 440475. (https://doi.org/10.1006/frne.1996.0012)

FergusonAVRenaudLP 1986 Systemic angiotensin acts at subfornical organ to facilitate activity of neurohypophysial neurons. American Journal of Physiology: Regulatory Integrative and Comparative Physiology 251 R712R717. (https://doi.org/10.1152/ajpregu.1986.251.4.R712)

FergusonSS 2001 Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacology Review 53 124.

FischerMBaesslerASchunkertH 2002 Renin angiotensin system and gender differences in the cardiovascular system. Cardiovascular Research 53 672677. (https://doi.org/10.1016/S0008-6363(01)00479-5)

FitzsimonsJT 1998 Angiotensin, thirst, and sodium appetite. Physiological Reviews 78 583686. (https://doi.org/10.1152/physrev.1998.78.3.583)

FleegalMASumnersC 2003 Drinking behavior elicited by central injection of angiotensin II: roles for protein kinase C and Ca2/calmodulin dependent protein kinase II. American Journal of Physiology: Regulatory Integrative and Comparative Physiology 285 R632R640. (https://doi.org/10.1152/ajpregu.00151.2003)

HaanwinckelMAEliasLKFavarettoALGutkowskaJMcCannSMAntunes-RodriguesJ 1995 Oxytocin mediates atrial natriuretic peptide release and natriuresis after volume expansion in the rat. PNAS 92 79027906. (https://doi.org/10.1073/pnas.92.17.7902)

HerbertJMAugereauJMGleyeJMaffrandJP 1990 Chelerythrine is a potent and specific inhibitor of protein kinase C. Biochemical and Biophysical Research Communications 172 993999. (https://doi.org/10.1016/0006-291X(90)91544-3)

HinesJFluhartySJYeeDK 2003 Structural determinants for the activation mechanism of the angiotensin II type 1 receptor differ for phosphoinositide hydrolysis and mitogen-activated protein kinase pathways. Biochemical Pharmacology 66 251262. (https://doi.org/10.1016/S0006-2952(03)00257-0)

HollenbergNK 1984 The renin-angiotensin system and sodium homeostasis. Journal of Cardiovascular Pharmacology 6 S176S183. (https://doi.org/10.1097/00005344-198400061-00028)

HrabovszkyEKalloIHajszanTShughruePJMerchenthalerILipositsZ 1998 Expression of estrogen receptor-beta messenger ribonucleic acid in oxytocin and vasopressin neurons of the rat supraoptic and paraventricular nuclei. Endocrinology 139 26002604. (https://doi.org/10.1210/endo.139.5.6024)

IglesiasAGSuárezCFeiersteinCDíaz-TorgaGBecu-VillalobosD 2001 Desensitization of angiotensin II: effect on [Ca2+]i, Inositol triphosphate, and prolactin in pituitary cells. American Journal of Physiology: Endocrinology and Metabolism 280 E462E470. (https://doi.org/10.1152/ajpendo.2001.280.3.E462)

JiHZhengWWuXLiuJEcelbargerCMWatkinsRArnoldAPSandbergK 2010 Sex chromosome effects unmasked in angiotensin II-induced hypertension. Hypertension 55 12751282. (https://doi.org/10.1161/HYPERTENSIONAHA.109.144949)

KisleyLRSakaiRRFluhartySJ 1999 Estrogen decreases hypothalamic angiotensin II AT1 receptor binding and mRNA in the female rat. Brain Research 844 3442. (https://doi.org/10.1016/S0006-8993(99)01815-6)

KohoutTALefkowitzRJ 2003 Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. Molecular Pharmacology 63 918. (https://doi.org/10.1124/mol.63.1.9)

KrauseEGCurtisKSDavisLMStoweJRContrerasRJ 2003 Estrogen influences stimulated water intake by ovariectomized female rats. Physiology and Behavior 79 267274. (https://doi.org/10.1016/S0031-9384(03)00095-7)

KrauseEGCurtisKSStincicTLMarkleJPContrerasRJ 2006 Oestrogen and weight loss decrease isoproterenol-induced Fos immunoreactivity and angiotensin type 1 mRNA in the subfornical organ of female rats. Journal of Physiology 573 251262. (https://doi.org/10.1113/jphysiol.2006.106740)

LemonnierJGhayorCGuicheuxJCaverzasioJ 2004 Protein kinase C-independent activation of protein kinase D is involved in BMP-2-induced activation of stress mitogen-activated protein kinases JNK and p38 and osteoblastic cell differentiation. Journal of Biological Chemistry 279 259264. (https://doi.org/10.1074/jbc.M308665200)

LenkeiZPalkovitsMCorvolPLlorens-CortesC 1997 Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review. Frontiers in Neuroendocrinology 18 383439. (https://doi.org/10.1006/frne.1997.0155)

MehtaPKGriendlingKK 2007 Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. American Journal of Physiology: Cell Physiology 292 C82C97. (https://doi.org/10.1152/ajpcell.00287.2006)

MenetonPJeunemaitreXde WardenerHEMacGregorGA 2005 Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases. Physiological Reviews 85 679715. (https://doi.org/10.1152/physrev.00056.2003)

MicevychPEKellyMJ 2012 Membrane estrogen receptor regulation of hypothalamic function. Neuroendocrinology 96 103110. (https://doi.org/10.1159/000338400)

MutaKMorganDAGrobeJLSigmundCDRahmouniK 2016 mTORC1 signaling contributes to drinking but not blood pressure responses to brain angiotensin II. Endocrinology 157 31403148. (https://doi.org/10.1210/en.2016-1243)

PaxinosGWatsonC 1997 The Rat Brain in Stereotaxic Coordinates. San Diego, CA, USA: Academic Press.

QadriFWaldmannTWolfAHöhleSRascherWUngerT 1998 Differential contribution of angiotensinergic and cholinergic receptors in the hypothalamic paraventricular nucleus to osmotically induced AVP release. Journal of Pharmacology and Experimental Therapeutics 285 10121018.

Rosas-ArellanoMPSolano-FloresLPCirielloJ 1999 Co-localization of estrogen and angiotensin receptors within subfornical organ neurons. Brain Research 837 254262. (https://doi.org/10.1016/S0006-8993(99)01672-8)

SalojinKOraveczT 2007 Regulation of innate immunity by MAPK dual-specificity phosphatases: knockout models reveal new tricks of old genes. Journal of Leukocyte Biology 81 860869. (https://doi.org/10.1189/jlb.1006639)

SamuvelDJJayanthiLDBhatNRRamamoorthyS 2005 A role for p38 mitogen-activated protein kinase in the regulation of the serotonin transporter: evidence for distinct cellular mechanisms involved in transporter surface expression. Journal of Neuroscience 25 2941. (https://doi.org/10.1523/JNEUROSCI.3754-04.2005)

SandbergKJiH 2012 Sex differences in primary hypertension. Biology of Sex Differences 3 7. (https://doi.org/10.1186/2042-6410-3-7)

SaraivaLFrescoPPintoEGonçalvesJ 2003 Isoform-selectivity of PKC inhibitors acting at the regulatory and catalytic domain of mammalian PKC-alpha, -beta1, -delta, -eta and -zeta. Journal of Enzyme Inhibition and Medicinal Chemistry 18 475483. (https://doi.org/10.1080/14756360310001603158)

ShortMDFoxSMLamCFStenmarkKRDasM 2006 Protein kinase Czeta attenuates hypoxia-induced proliferation of fibroblasts by regulating MAP kinase phosphatase-1 expression. Molecular of Biology Cellular 17 19952008. (https://doi.org/10.1091/mbc.e05-09-0869)

SloneSAnthonySRWuXBenoitJBAubeJXuLTranterM 2016 Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy. Cellular Signalling 28 17351741. (https://doi.org/10.1016/j.cellsig.2016.08.005)

SomponpunSSladekCD 2002 Role of estrogen receptor-beta in regulation of vasopressin and oxytocin release in vitro. Endocrinology 143 28992904. (https://doi.org/10.1210/endo.143.8.8946)

SomponpunSJHolmesMCSeckJRRussellJA 2004 Modulation of oestrogen receptor-b mRNA expression in rat paraventricular and supraoptic nucleus neurones following adrenal steroid manipulation and hyperosmotic stimulation. Journal of Neuroendocrinology 16 472482. (https://doi.org/10.1111/j.1365-2826.2004.01190.x)

StawowyPGoetzeSMargetaCFleckEGrafK 2003 LPS regulate ERK1/2-dependent signaling in cardiac fibroblasts via PKC-mediated MKP-1 induction. Biochemical and Biophysical Research Communications 303 7480. (https://doi.org/10.1016/S0006-291X(03)00301-2)

StrickerEMThielsEVerbalisJG 1991 Sodium appetite in rats after prolonged dietary sodium deprivation: a sexually dimorphic phenomenon. American Journal of Physiology: Regulatory Integrative and Comparative Physiology 260 R1082R1088. (https://doi.org/10.1152/ajpregu.1991.260.6.R1082)

SwensonKLSladekCD 1997 Gonadal steroid modulation of vasopressin secretion in response to osmotic stimulation. Endocrinology 138 20892097. (https://doi.org/10.1210/endo.138.5.5142)

Takeda-MatsubaraYNakagamiHIwaiMCuiTXShiuchiTAkishitaMNahmiasCItoMHoriuchiM 2002 Estrogen activates phosphatases and antagonizes growth-promoting effect of angiotensin II. Hypertension 39 4145. (https://doi.org/10.1161/hy1201.097197)

TanakaCNishizukaY 1994 The protein kinase C family for neuronal signaling. Annual Review of Neuroscience 17 551567. (https://doi.org/10.1146/annurev.ne.17.030194.003003)

PubMed

Google Scholar