Mineralocorticoid Regulation of Cell Function: the Role of Rapid Signalling and Gene Transcription Pathways

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g s y ong and m j young Mineralocorticoid cell signalling 58: 1 R33–R57 Review

Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways

Gregory S Y Ong1,2 and Morag J Young1,3

1 Cardiovascular Endocrinology Laboratory, Centre for Endocrinology and Metabolism, Hudson Institute Correspondence of Medical Research, Clayton, Victoria, Australia should be addressed 2 Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia to M J Young 3 Department of Physiology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia Email [email protected]

Abstract

The mineralocorticoid receptor (MR) and mineralocorticoids regulate epithelial handling Key Words of electrolytes, and induces diverse effects on other tissues. Traditionally, the effects ff aldosterone of MR were ascribed to ligand–receptor binding and activation of gene transcription. ff mineralocorticoid However, the MR also utilises a number of intracellular signalling cascades, often by receptor transactivating unrelated receptors, to change cell function more rapidly. Although ff glucocorticoid aldosterone is the physiological mineralocorticoid, it is not the sole ligand for MR. ff MAPK pathways Tissue-selective and mineralocorticoid-specific effects are conferred through the ff GPER ff EGFR enzyme 11β-hydroxysteroid dehydrogenase 2, cellular redox status and properties of the MR itself. Furthermore, not all aldosterone effects are mediated via MR, with implication of the involvement of other membrane-bound receptors such as GPER.

Journal of Molecular Endocrinology This review will describe the ligands, receptors and intracellular mechanisms available for mineralocorticoid hormone and receptor signalling and illustrate their complex Journal of Molecular interactions in physiology and disease. Endocrinology (2017) 58, R33–R57

Introduction

The mineralocorticoid receptor (NR3C2, henceforth The MR can change cell function through multiple abbreviated MR) and mineralocorticoids regulate means. Edelman first proposed that aldosterone modifies numerous physiological processes including control of sodium transport via gene transcription (Edelman et al. electrolytes, extracellular volume and blood pressure 1963), a mechanism recently confirmed as critical (Waldinger et al. 1977), intracellular pH (Oberleithner et al. for life-sustaining salt homeostasis (Cole et al. 2015). 1987), cardiac action potentials (Lalevee et al. 2005, MR activation also triggers rapid responses that are Boixel et al. 2006) and vascular function (Liu et al. 2003, impervious to transcription inhibitors, suggesting a non- Uhrenholt et al. 2003, Gros et al. 2013) among others. The genomic action (Moura & Worcel 1984, Le Moellic et al. MR also contributes to cardiovascular and renal disease. 2004). Furthermore, mineralocorticoids may activate Primary hyperaldosteronism (PA), a cause of secondary receptors other than the ‘classic’ cytosolic MR: either as hypertension due to chronic excessive aldosterone a ligand of a different cell membrane-associated receptor, synthesis, is associated with increased mortality and or by influencing signalling of unrelated receptors such morbidity independent of the degree of hypertension as angiotensin II receptor 1 (AGTR1). These systems do (Milliez et al. 2005). not occur in isolation, and may enable, complement,

10.1530/JME-15-0318 Journal of Molecular Endocrinology structure allowseachreceptor inthedimertobinda similar tothatfortheGR( structure oftheMRDBDwhenboundtoaHREis crystal described inthatcontext ( A). TheHREscouldalsobind GR;theywereoriginally regulate transcriptionoftargetgenes( known ashormoneresponseelements(HREs), to Nishi 2011 expression ( availability, cell-specificsteroidhandling and receptor activated MRandGR,whichisinfluencedbyhormone heterodimerisation dependsontherelativeabundance of in differenttranscriptionalresponses.Thedegree of homodimers, butalsoheterodimeriseswithGR,resulting 2004 ( from itschaperonestoallowbindingDNA 2010 shuttling ofMRafterligandbinding( to MR,whileFKBP52isimportantincytoplasmic–nuclear 2010 as FKBP52) and protein phosphatase 5 ( proteins (HSPs)suchasHSP90,immunophilins(such part ofaheterocomplexwithchaperoneheatshock predominantly inthecytosol( ( to modify transcriptional function molecules which serve together withAF-2sitesintheLBD,canbindco-regulatory (AF-1a andAF-1b)sites,interactwithnuclearproteins,and, outcomes. TheNTD,viaitsactivationfunction-1 interaction, butotherpartsoftheirstructurecanaffect hormone receptors areactivated through ligand–LBD binding domain(LBD).TheMRandothersteroid binding domain (DBD), hinge region and a ligand- contain an amino terminal domain (NTD), DNA- receptor (PGR)( (NR3C1, henceforthabbreviatedGR)andprogesterone structural similaritiestotheglucocorticoidreceptor transcription factorsuperfamilyandretainssignificant In humans,theMRispartofasteroid-activated The structure andfunctionoftheMR and disease. characterise theiractionsandcontributiontophysiology the keymechanismsofmineralocorticoidactionand at severallevels,thepurposeofthisreviewistoidentify augment orabrogateeachother. Giventhecomplexity Pippal &Fuller2008 Galigniana DOI: 10.1530/JME-15-0318 http://jme.endocrinology-journals.org Review The MR DBD binds to specific DNA sequences, In thebasalorunligandedstate,MRislocated , b a ). Onceinthenucleoplasm,MRdissociates , Grossmann Huyet ). Nishi et al et al Arriza . 2010 . 2012 t al et t al et ). t al et a . 2012 ). HSP90facilitatesligandbinding . 2004 ) andformsdimers( Hudson . 1987 ). TheMRnotonlyforms Payvar , Rogerson Ackermann g

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transcription factorsthathaveknownbindingsitesin regulation. Instead,MRmayformcomplexeswithother forMRgenomic HRE sequence,HREsarenotmandatory many areasofDNAwhichlackapartialorfullclassical specifically ( MR thanGR( can preferentiallyenhancetranscriptioninresponseto & Yamamoto 1993 structure andtargetDNAsequencerecognition( and GRdespitetheoverlapinligandbinding,receptor some ofthedifferencesingeneregulationbetweenMR Interaction withco-factorsattheNTDmayexplain (PAX5) ( 1 (EGR1),forkheadbox(FOX)andpairedprotein5 activated protein-1(AP-1),earlygrowthresponseprotein binding ofnon-hormonetranscriptionfactorssuchas sequences adjacenttotheconsensusmotifsfacilitate ( ‘half-site’ ofthepalindromicconsensussequence fluid, mechanismsmust exist toconferspecificity of mineralocorticoids inthe circulation andintracellular glucocorticoids aresubstantially moreabundantthan order landanimals( and glucocorticoidhormones andreceptorsinhigher- primitive marineanimalstodistinctmineralocorticoid single multifunctionalcorticosteroidreceptor(CR) in be avestigeofevolution,withprogressionfrom a steroid progesterone( is criticalforprotectionagainsthypovolaemia( it isdeficient( of life-threateningsaltwastingandhyperkalaemiawhen and itsimportanceisdemonstratedbytheneonatalonset Aldosterone isthemajorphysiologicalmineralocorticoid ligand-specific effects of MR Pre-receptor andreceptor mechanismsdetermining itself ( these HRE-freeregions,ratherthandirectlybindingDNA corticosterone ( high affinityfortheglucocorticoidscortisoland 1958 tubular epithelialcells( ofrenal by alteringthesodiumtransportmachinery function inregulatingsaltandfluidbalanceisachieved levels andadrenocorticotropichormone(ACTH).Its renin–angiotensin system(RAS),extracellularpotassium of theadrenalgland under theregulation of the 2014 Mineralocorticoid cellsignalling Nishi Published byBioscientifica Ltd. Apart fromaldosterone,thehumanMRhas , ). Aldosteroneissynthesisedinthezonaglomerulosa Beuschlein 2013 Le Billan et al Pearce &Yamamoto 1993 . 2004 Meinel Daughaday &Rendleman1967 Kolla et al Pearce & , Grossmann . 2015 , et al t al et Lim-Tio ). Quinkler Baker Loffing &Korbmacher2009 . 2013 Downloaded fromBioscientifica.com at09/27/202102:29:00PM . 1999 ).

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Review g s y ong and m j young Mineralocorticoid cell signalling 58:1 R35

Figure 1 Overview of the cellular responses to MR activation. (A) Once activated, the mineralocorticoid receptor (MR) translocates to the nucleus and transcribes target genes including SGK1, sodium channel subunits and receptors such as the MR gene (NR3C2), epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF1R) and angiotensin II receptor 1 (AGTR1). Some gene targets are intermediaries that activate other transcription factors. (B) Alternatively, aldosterone and MR act via second messenger systems, often by activating unrelated receptors in the absence of their ligands. Note, the MR may also signal via other MAPK cascades (JNK and p38MAPK) but only the ERK cascade is shown here. Additionally, aldosterone may act in an MR independent manner – potentially by directly binding to and activating unknown membrane receptors instead. GPER is one such proposed receptor, although MR binding to it has not been definitively demonstrated. (C) RAC1 and AGTR1 can also activate MR signalling and gene transcription in certain circumstances, in the absence of any ligand binding to MR. Some signalling pathways are redox sensitive and enabled or enhanced by NADPH oxidase

Journal of Molecular Endocrinology (NOX) production of reactive oxygen species (ROS).

effect at the MR. The enzyme 11-beta-hydroxysteroid expression. Glucocorticoids inhibit eNOS transcription, dehydrogenase type 2 (HSD11B2) is co-expressed with which is exacerbated by HSD11B2 knockdown in a MR in epithelial cells, metabolising cortisol to cortisone, human umbilical vein endothelial cell (HUVEC) line which cannot bind or activate the MR (Funder et al. (Liu et al. 2009). 1988). This is crucial for the specificity of aldosterone Generally, in tissues where HSD11B2 is not expressed, as the regulator of fluid homeostasis. If HSD11B2 is glucocorticoids are the physiological ligand for the MR deficient or inhibited, hypertension and hypokalaemia (Iqbal et al. 2014). An exception occurs where the related develop due to cortisol activation of renal MR (Koster enzyme HSD11B1 is expressed, without co-expression & David 1968, Dave-Sharma et al. 1998, Mullins et al. of hexose-6-phosphate dehydrogenase (H6PD). H6PD 2015). In the vasculature, endothelial cells can express generates the reduced form of nicotinamide adenine HSD11B2 (Brem et al. 1998, Christy et al. 2003, Gong et al. dinucleotide phosphate (NADPH), without which 2008), while the literature is conflicting regarding its HSD11B1 shifts its role from reductase to dehydrogenase, presence in vascular smooth muscle cells (VSMCs) metabolising cortisol to cortisone (Hewitt et al. 2005, (Hatakeyama et al. 2001, Christy et al. 2003). Deficiency Chen et al. 2014). Transgenic mice overexpressing or inhibition of HSD11B2 impairs endothelium-mediated HSD11B2 in cardiomyocytes develop dilated vasodilation, but glucocorticoid occupation of MR may cardiomyopathy and fibrosis, which is attenuated with not be the cause (Christy et al. 2003, Sobieszczyk et al. MR antagonism (Qin et al. 2003), implying that basal 2010). Instead, a potential mechanism may involve cardiac MR occupancy by endogenous glucocorticoid is regulation of endothelial nitric oxide synthase (eNOS) protective against activation. However, in situations of

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-15-0318 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 02:29:00PM via free access Journal of Molecular Endocrinology those relatedtoelectrolyte handlinginrenalepithelial ( ( duration, magnitudeandcontext ornatureoftheeffect change. Thesemechanisms allowdiversityintiming, The MRutilisesseveralmechanismstoeffectcellular Expression ofMRtargetgenes cellular processes How the activated MRchanges with MRoveractivity. these RAC1mechanisms,and establish the molecular link ( aortic constrictionmodelofcardiacpressureoverload sensitive Dahlrats( ( activation, canoccurinthecontextofoxidativestress RAC1 activation,withassociatedligand-independentMR hormone receptorsincludingtheMR( is involvedinROSgenerationandcanactivatesteroid which regulatemanycellularprocesses.Importantly, it 1 (RAC1)ispartoftheRhofamilysmallGTPases, ligand binding.Ras-relatedC3botulinumtoxinsubstrate MR activationandnucleartranslocationtooccurwithout Gallo MR targetgenetranscription( having greater potency than cortisol for inducing effectively recruitco-regulators,resultinginaldosterone stabilises theMRinaconformationthatcanmore a comparativelylongerperiodthancortisol,which Young 2009 facilitate nuclear localisation and transcription ( changes conformationandrecruitsotherelementsto 2005 binding affinityandtranscriptionalactivity( residues ontheLBDandsteroiddetermineligand LBD pocket shape and van der Waal forces between the outcometoligandbindingatreceptor. TheMR final responseoftheMRtoligandactivation. expression andtheredoxstatusofcellsdetermine Hence, theavailabilityofligand,distributionHSD11B2 blockade ofMR( are notsolelyfromaldosteroneantagonism,butgeneral benefits ofspironolactoneoreplerenoneinheartfailure ( or ischaemia,glucocorticoidscanactivatetheMR intracellular oxidativestress,suchaswithinflammation Fig. 1 1 Fig. Rossier Ayuzawa Nagase DOI: 10.1530/JME-15-0318 http://jme.endocrinology-journals.org Review The intrinsicpropertiesoftheMRstructureinfluence , et al , sectionA),withwell-established MRtargetsbeing ). MRregulatesthetranscription ofmanygenes Mani et al et al et al . 2007 . 2008 . 2012 ). AldosteroneremainsboundtoMRfor t al et . 2015 , Pitt . 2016 Huyet , ) ( Shibata Mihailidou ). Furtherworkisrequiredtoconfirm Fig. 1 et al ). Afterligandbinding,theMR et al . 1999 , sectionC),saltloadinginsalt- et al . 2012 , . 2011 et al 2003 Hellal-Levy g

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tissues, suchassodiumchannelsortransporters( triggered byMRactivation ( and c-jun N-terminal kinase (JNK) all of which can be signal-regulated kinase(ERK),p38(p38MAPK) mammals, the key families of MAPK are extracellular Gene transcriptionandproteintranslationisarelatively Rapid signallingthrough secondmessengersystems functional outcomesoftheirregulationbyMR. further investigation to establish the mechanism and 2010 GR- and MR-regulated genes in the heart ( or MRsuggeststhatthereissurprisinglylittleoverlapin between micewithcardiacoverexpressionofeitherGR Newfell migration ( receptor chaperoning,cellularstructure,adhesionand mediators,steroidbiosynthesis, stress, inflammatory diverse functionsincellsignaltransduction,oxidative cardiac tissueafterexposuretoaldosterone.Thesehave through transcriptomeanalysesonrenal,aorticand 2001 and cellularelectrolytehandling ( in thedevelopingneonatal ratkidney( for MR-mediatedcellproliferation orapoptosis,suchas 2009 membrane receptor)totheinterior( MAPK relayssignalsfromthecellsurface(e.g. a processes. Asacascadeofsequentiallyactivatedkinases, activation ofproteinstoregulatenumerousdiversecellular and protein kinases,whichcatalysephosphorylation MAPKs areagroupofserine/threoninecytoplasmic Mitogen-associated proteinkinases(MAPK) to initiatetheserapideffects( 2000 transcribed MR target gene ( glucocorticoid-regulated kinase1( the 30 ( epithelial sodiumchannel(ENaC)activitywithin2 non-genomic means.Forinstance,aldosteroneincreases activation cantriggermorerapidcellulareventsthrough disturbance isrequired,suchasduringhaemorrhage.MR inadequate whenarapidhomeostaticresponsetoacute for membrane-based sodium channels). This would be export, translocationandassemblyisrequired(suchas before anyfunctionalchange,ifproteinsynthesis, slow process.Adelayofseveralhoursmaytranspire Mineralocorticoid cellsignalling Zhou & Bubien 2001 Published byBioscientifica Ltd. ). Novelgenesidentifiedintheseexperimentsrequire ). FurthercandidateMRtargetgenesareproposed , ). The MR is able to utilise second messenger systems Walczak min requiredformRNAexpressionofserumand t al et Turchin . 2011 et al . 2011 t al et , ), which is significantly faster than Ueda Downloaded fromBioscientifica.com at09/27/202102:29:00PM ). MAPKsignallingisimportant . 2006 Naray-Fejes-Toth & Fejes-Toth Nagai Fig. 1 t al et , Latouche . 2014 , sectionB). et al Gekle SGK1 58 Roskoski 2012 . 2005 : Yim 1 ). Comparison Latouche ), a‘rapidly’ t al et t al et et al , Han Mick . 2009 . 2001 . 2010 R36 et al et al ). In et al min via freeaccess ), . . , . ,

Review g s y ong and m j young Mineralocorticoid cell signalling 58:1 R37

McEneaney et al. 2008). The ERK cascade (RAS-RAF-MEK- other receptors, which trigger downstream signalling ERK) is rapidly activated within 2–5 min by aldosterone similar to activation by their own ligand. Although these (Gekle et al. 2001, McEneaney et al. 2010a); JNK can transactivated receptors share second messenger systems, similarly be activated within 5 min (Han et al. 2009), and their effects are not identical due to differences in receptor p38 MAPK within 10 min (Lee et al. 2004). Initial rapid expression and the specific context required for activation ERK1/2 activity lasts around 30 min (Nagai et al. 2005), but (particularly redox status). These effects span the full time can be extended to around 2 h in a protein kinase D (PKD)- course of cellular events from rapid posttranslational dependent mechanism (McEneaney et al. 2010a), with modifications to slower gene transcription Wang ( et al. further prolongation of the response to 4–6 h requiring 2001, Holzman et al. 2007, Cascella et al. 2010). transcription of Kirsten Ras (K-Ras) mRNA (Hendron & Stockand 2002). Less is known about prolonged activation Epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor of the other MAPK cascades by MR. (PDGFR) The EGFR is a transmembrane receptor tyrosine Phosphatidylinositide lipid and protein kinase kinase, which, along with structurally similar receptor messenger system Phosphatidylinositide 3-kinases tyrosine kinases such as HER2, ErbB3 and ErbB4, is part of (PI3K) activity is stimulated by aldosterone, which the ErbB family. When activated, EGFR homodimerises or phosphorylates membrane phosphatidylinositol and heterodimerises with another member of the ErbB family, generates phosphatidylinositol 3,4,5-trisphosphate triggering autophosphorylation of tyrosine residues in (PIP3) (Blazer-Yost et al. 1999). PIP3 is required to its cytoplasmic domains and activation of associated activate phosphatidylinositol-dependent kinases (PDK) intracellular signalling cascades (Mirone et al. 2015). and ultimately Akt as the effector of PI3K-dependent These include MAPK, Janus kinase/signal transducers cellular processes (Ghigo & Li 2015). MR-dependent Akt and activators of transcription (JAK/STAT) and PI3K/Akt phosphorylation occurs within 15 min of aldosterone (Mirone et al. 2015). EGFR, a mediator of growth and exposure, suggesting that PI3K/Akt is a pathway for repair, is a recognised contributor to renin–angiotensin– MR-mediated rapid effects (Huang et al. 2012) including aldosterone system (RAAS)-driven cardiac and renal fibrosis electrolyte handling and vasomotor function. (Zhuang & Liu 2014, Forrester et al. 2016). Aldosterone activates EGFR in a non-MR-dependent process within Protein kinases C (PKC) and D PKC and PKD form 10 min, triggering the ERK cascade and ultimately part of a regulatory signalling cascade, commonly under causing calcium influx and cellular alkalinisation through

Journal of Molecular Endocrinology the regulation of G-protein coupled surface receptors. increased activity of the sodium/hydrogen exchanger Activation of the PKCε subtype leads to phosphorylation (NHE)-1 (Gekle et al. 2002). Aldosterone activation of of PKD at two critical activating sites leading to other multifunctional signalling pathways via EGFR, downstream effects including membrane trafficking, such as the JNK pathway (Grossmann et al. 2005) and cell survival, cell migration and interaction with MAPK PI3K/Akt (Huang et al. 2009), are MR dependent. The cascades (Rozengurt et al. 2005). MR uses PKC and PKD signalling process is influenced by the cellular redox state, signalling to alter electrolyte handling in renal epithelial in that the antioxidant N-acetylcysteine (NAC) prevents cells and in cardiomyocytes (Mihailidou et al. 2004, downstream effects of aldosterone–MR transactivation of McEneaney et al. 2008). EGFR on PI3K (Huang et al. 2009). As illustrated in Fig. 1 section B, the link between MR and EGFR activation is the non-receptor tyrosine kinase, Interaction with other hormone receptor systems c-Src, which phosphorylates a tyrosine residue at position The intracellular signalling cascades induced by MR 845 on EGFR (Grossmann et al. 2005, McEneaney et al. activation are complex and intricately intertwined. 2007). Aldosterone rapidly increases c-Src phosphorylation Mapping discrete pathways linking MR to cellular within 5 min and has maximal response at 30 min outcomes is difficult due to the extent of cross-talk (Callera et al. 2005). Furthermore, c-Src activation by MR between the elements, and their occasionally opposing may be dependent on the PDGFR in a complex interaction effects. This difficulty is further exacerbated when occurring within cellular invaginations, termed caveolae. considering the involvement of other receptor systems in Here, the transactivation of PDGFR by MR facilitates this process. In many cases, second messenger systems are translocation of c-Src to cholesterol-rich domains and its not directly activated by MR. Instead the MR transactivates phosphorylation (Callera et al. 2011b). Another potential

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-15-0318 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 02:29:00PM via free access Journal of Molecular Endocrinology as an intermediary ( as anintermediary not require MR to transactivate IGF1R, but utilises c-Src 2007 renal epithelialcells( within 10 2008 beta islet cell function and malignancy ( cardiovascular function,insulinresistanceandpancreatic protein ofthegrowthhormonesystem,butisinvolvedin ligand, IGF-1,isnotonlyimportantastheeffector and metabolismthroughPI3K/Aktsignalling.Itsprimary regulation ofcellgrowthmainlythroughMAPKsignalling, IGF1R isubiquitouslyexpressedandimportantinthe Insulin-like growth factor-1 receptor (IGF1R) prolonged MRactivation. events couldpotentiateEGFR-relatedsignallingfrom shuttling ( ERK1/2 signallingisanimportantfacilitatorofMRnuclear 2003 expression isupregulatedbyMRactivation( between MRandtheEGFR.Asantargetgene,EGFR 2016 sympathetic activity. AGTR2hasopposingeffects aldosterone production,salt/fluid retentionandincreased species (ROS)generation, vascular cellproliferation, angiotensin IIsuchasvasoconstriction, reactiveoxygen AGTR1 isassociatedwithclassical functionsascribedto primarily throughtworeceptors:AGTR1andAGTR2. and amajorsecretagogueforaldosterone.Itacts II isanimportanteffectorproteinoftheRAASsystem Angiotensin IIreceptor1(AGTR1) ( promoting VSMC growth, migration and protein synthesis oxidative stress,withenhanceddownstreamsignalling can beupregulatedbyMR,particularlyinconditions of for MR action ( systems toMR,theIGF1Risacandidateintermediary via PI3K,andcanactivatesimilarsecondmessenger mimic somealdosteroneeffectsonrenalsodiumhandling not yetcharacterised( IGF1R transactivationrequiresMR,butthemechanismis ( phosphorylation the G-proteinsubunitG G-protein coupledreceptor, assiRNAknockdownof c-Src infibroblastsmay dependonasurfacemembrane one ER-negativebreastcancercellline( which isrequiredfor MR–EGFR transactivation at leastin link istheG-proteincoupledoestrogenreceptor(GPER), Cascella DOI: 10.1530/JME-15-0318 http://jme.endocrinology-journals.org Review , ofIGF1R ). Aldosteroneinducesphosphorylation , ). Furthermore,thereisasynergisticrelationship Meinel Chen et al min in renal and cardiac fibroblasts, and in Grossmann et al . 2010 et al Blazer-Yost . 2013 . 2013 Bunda ). Chen Bunda Holzman et al ). Infibroblasts,aldosteronedoes a ). Conversely, EGFR activation of α t al et 13 . 2005 et al et al preventedc-Src andIGF1R t al et . 2009 . 2013 . 1999 et al g ). These complementary ). Thesecomplementary

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young The t al et t al et t al et et al . . . . in cardiomyocytes( needsbothMRandAGTR1 induced ERKphosphorylation for example,incontrasttovascularcells,aldosterone- of theMR-AGTR1interactionvariesbetweencelltypes: both ligands ( common molecular signalling mechanism spanning activation, thecross-talkbetweenMRandAGTR1isa 2009 a critical intermediary ( a criticalintermediary of AGTR1, with the transglutaminase enzyme as AGTR1 isunknown.Aldosterone triggersdimerization how mineralocorticoidsand theMRcouldtransactivate pathways. Apartfromthecontribution ofc-Src, exactly c-Src linksMRandmultipleotherreceptorsignalling Hence, inthecorrectenvironmentandcellcontext, and finally VSMC migration ( to thecellmembrane,ROS-dependentactivationofRhoA NADPH oxidase(NOX),translocationofRhoA/Rhokinase processes are also activated, such as generation of ROS by individually donotaltercellsignalling.Downstream of angiotensinIIandaldosteroneatlowdosesthat with activationofc-Src canbetriggeredbysynergism ( important linkbetweenMR,AGTR1andtheERKcascade analogous tothemousesubtypes( literature regardingtheirexistenceandwhethertheyare of AGTR1subtypestohumansisunclear, withlittleinthe to wildtypeinVSMCs( transcription factor, inresponsetoaldosteronecompared AGTR1a reducestranscriptionofc-fos,arapidlyinduced of aldosterone-mediatedgenomiceffects.Knockout AGTR1a hasalsobeenidentifiedasanimportantfacilitator are neededforNF- not AGTR1b or MR dependent, but both AGTR1 subtypes aldosterone activation ofERK1/2andJNKwasAGTR1abut pathways. InmousemesentericVSMCs,angiotensinIIand which have differing effects on downstream signalling regulates numerous inflammatory genes ( regulates numerous inflammatory activated Bcells(NF- of thenuclearfactorkappa-light-chain-enhancer However, AGTR1andMRarebothrequiredforactivation independent ( and rapidvasoconstrictionrequiresAGTR1,butisMR mesenteric vessels,aldosterone-inducedERKactivation by mineralocorticoidsandangiotensinII.Inmouse AGTR1 andMRplayaroleinrapidsignallingtriggered promotion ofapoptosis( including vasodilation,nitricoxide(NO)generationand Mineralocorticoid cellsignalling Cannavo Published byBioscientifica Ltd. As withEGFR/PDGFRandIGF1R,c-Src isan In rodents,AGTR1occursastwosubtypes(aandb) ). AsangiotensinIIalsorequiresMRforNF- t al et Lemarie Yamada . 2016 Cannavo κ B activation( κ ). Infact,EGFR/PDGFRsignalling B), atranscriptioncomplexwhich Lemarie et al t al et Downloaded fromBioscientifica.com at09/27/202102:29:00PM Vinturache &Smith2014 Yamada . 2009 . 2008 et al et al Montezano . 2016 ). However, the nature , Konishi Lemarie . 2009 Lemarie t al et 58 ). : 1 . 2008 ). Therelevance et al Lemarie t al et t al et t al et . 1994 ); given . 2008 . 2009 . 2009 ). Both R38 t al et ). κ via freeaccess ). ). ). ). B . Review g s y ong and m j young Mineralocorticoid cell signalling 58:1 R39

that transglutaminase activity is calcium-dependent, G-protein coupled oestrogen receptor (GPER, aldosterone-induced calcium influx may be an early also known as GPER-1 or GPR30) As many cellular regulator of AGTR1 transactivation. It is not clear if this is signalling cascades relay information from membrane an MR-dependent effect or not. Further research is needed surface to the interior, it was believed that a distinct to confirm this theory and to characterise the remaining membrane-bound MR exists. Radiolabelled binding components of the pathway. assays showed mineralocorticoid binding to the plasma The relationship among aldosterone, angiotensin II, membrane of porcine renal cells and human monocytes MR and AGTR1 serves to mutually enhance the signalling with higher affinity than other steroids Wehling ( et al. of each individual ligand–receptor system. Aldosterone is 1991, Christ et al. 1994). Furthermore, bovine serum able to upregulate the expression of both MR and AGTR1 albumin (BSA)-conjugated aldosterone triggers PKCα (Schiffrin et al. 1985, Zennaro et al. 1996, Tsai et al. 2013). signalling (Le Moellic et al. 2004) and polyethylene glycol In cardiomyocytes, aldosterone control of MR expression (PEG)-conjugated aldosterone activates ERK, despite both is dependent on MR coupled to AGTR1 signalling and being too large to enter the cell to activate classical cytosolic downstream ERK and JNK activation, whereas AGTR1 MR (Ashton et al. 2015). Differential action of classical expression is regulated by MR-independent transactivation and alternative receptors is suggested by the latter study, of AGTR1 signalling (Tsai et al. 2013). Furthermore, where PEG–aldosterone could not upregulate classical MR aldosterone activation of MR increases transcription of target genes such as SGK1, yet unconjugated aldosterone angiotensin-converting enzyme (ACE) mRNA in the aorta could both upregulate SGK1 and activate ERK. However, of rats treated with aldosterone (Hirono et al. 2007) and in numerous experiments have failed to identify a unique cultured rat aortic endothelial cells (Sugiyama et al. 2005). membrane-bound MR. Instead, GPER is proposed as an This process is JAK2 dependent and requires downstream alternative candidate for mineralocorticoid signalling. c-Src signalling and transactivation of EGFR. The resultant GPER is a G-protein coupled receptor that is expressed increase in local angiotensin II levels exacerbates in numerous tissues such as cardiomyocytes, VSMCs, endothelial dysfunction and damage (Sugiyama et al. vascular endothelium, lung, liver and reproductive tissues 2005). ACE expression in cardiomyocytes is similarly (Prossnitz et al. 2007, Jessup et al. 2010, Gros et al. 2011b). enhanced by MR (Harada et al. 2001, Wang et al. 2002). 17β-Oestradiol (E2) was the first known ligand for GPER, However, the practical relevance of local ACE activity to which is responsible for some of the rapid effects of E2 vasomotor function is uncertain given that aldosterone- via MAPK (Filardo et al. 2000), and via PI3K signalling induced mesenteric vasoconstriction ex vivo is not mediated by EGFR transactivation (Revankar et al.

Journal of Molecular Endocrinology mitigated by ACE inhibition (Yamada et al. 2008). 2005). In GPER-transfected human embryonic kidney In a bilateral relationship, angiotensin II can cells, which lack native oestrogen receptors, E2 exhibits transactivate MR via AGTR1 and increase transcription rapid association/dissociation and high-affinity binding of MR-dependent genes, a process that can be suppressed to the recombinant human GPER with a dissociation

by spironolactone (Jaffe & Mendelsohn 2005). AGTR1 constant (Kd) of 2.7 nM (Thomas et al. 2005). In an ex vivo transactivation of MR may involve RAC1, which is highly experiment, E2 concentrations of 0.1–10 nM are capable activated in a mouse model of salt and angiotensin II excess of inducing GPER-mediated changes to calcium handling (Fig. 1, section C). In this scenario, RAC1 inhibition reduces in the renal connecting tubule (Hofmeister et al. 2012). MR nuclear localisation and SGK1 transcription to the GPER may also be responsible for a subset of same extent as eplerenone (Kawarazaki et al. 2012). Local aldosterone’s rapid cellular actions involving ERK production of aldosterone is not involved, as angiotensin signalling in rat aortic VSMCs (Gros et al. 2011b), II-treated VSMCs do not express aldosterone synthase and endothelial cells (Gros et al. 2013) and rat H9C2 gene expression is not altered by aldosterone synthase cardiomyocytes (Ashton et al. 2015). In these tissues, inhibition (Jaffe & Mendelsohn 2005). Conversely, MR aldosterone activation of ERK could occur through acts via AGTR1 to upregulate profibrotic markers such either MR or GPER (Fig. 1, section B). Evidence for GPER as collagen 1A (COL1A) and 3A (COL3A) and α-smooth signalling includes the maintenance of phosphorylation muscle actin (SMA) (Tsai et al. 2013). Therefore, the MR of ERK in rat endothelial tissue lacking MR (Gros et al. and AGTR1 are intertwined at multiple points facilitating 2013), despite the eplerenone treatment in native GPER cooperation of different effector systems of RAAS with and MR expressing freshly isolated endothelium-denuded implications for both homeostasis and in disease states. rat aorta (Gros et al. 2011b). Yet, ERK activation is inhibited

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-15-0318 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 02:29:00PM via free access Journal of Molecular Endocrinology activity leadstoexcessive and dysfunctionalactivation ( ion transport,genetranscription, cellgrowthanddeath enzymaticreactions,cellular protein phosphorylation, functions including altering has numerous regulatory GPER ( adenoviral transfection,MRpredominantlyactsthrough MR alone.However, whenGPERisreintroducedthrough this contextaldosteronecantriggerERKsignallingvia cultures tendtoloseGPERexpressionovertime,andin ROS generation ( or AGTR1antagonism,and does notaffectMR-mediated toalesserdegreethanMR inhibits ERKphosphorylation cultures ofratventricularmyocytes,GPERblockade mediated ERKactivationvariesbycelltype.Inprimary co-expressed, therelativecontributiontoaldosterone- Ashton ( found incardiomyocytes,endothelialcellsandVSMCs required for the antimicrobial oxidative burst. It is also NOX ispresentinleucocytes,wheresuperoxide is which generatesuperoxidefromNADPHandoxygen. NOX. NOXisafamilyofmembrane-boundenzymes, by MRactivation,particularlythroughupregulation of alternative pathways.ThegenerationofROSisincreased status ofcellsisamajordeterminantMRaccesstothese to avoidnon-specificactivation.Inparticular, theredox cross-talk interactionsarenecessarilycontextdependent systems increasesthediversityofitsfunctions.These The MRactivationofothermembranereceptorsignalling NOX, ROSandMRsignalling hypotheses ( GPER antagonistisnotexplainedbythesealternative in tissueslackingordeficientMRandblockedby 2015 can modulatesteroidreceptorfunction( modification ofthestructuralprotein GPER inductionoflocalaldosteronesynthase,and ( direct physical association between MR and GPER mechanisms ofaldosteroneactionviaGPERmay include ( studies, binding has not been definitively demonstrated levels ofaldosterone(e.g.10 there is apparent activation of GPER at physiological whether aldosteroneisatrueligandofGPER.Although with GPERantagonismorknockdown( Bedard &Krause2007 Ying 2008 Rigiracciolo Cheng DOI: 10.1530/JME-15-0318 http://jme.endocrinology-journals.org Review ). However, thepersistenceofaldosteroneresponses Gros t al et t al et , . 2014 Feldman & Limbird2015 et al et al Santillo . 2015 . 2016 . 2011 Cannavo , ). WherebothGPERandMRare Rigiracciolo t al et ), cross-talkviasecondmessengers, b ). Thereisongoingdebateasto ). Indisease,enhancedNOX . 2015 t al et nM) intheabove-mentioned . 2016 g t al et ). NOX-generatedROS

ong . 2016 ). ). Primary VSMC ). Primary Gros and Barton &Meyer Printed inGreatBritain striatin ). Alternative m et al

young , which . 2011 b , remains importantforNOX2 synthesis,asknockoutof 2005 mesangial cells,endothelial cellsandheart( increasing synthesisofNOX cytosolicsubunitsinrenal generation ( mitochondrial localisationofGRK2whichpromotesROS AGTR1 interactionseparatelycontributesbyinducing effect( in afeed-forward turn triggersmitochondriatogenerateevenmoreROS utilises thePI3K/AktcascadetoactivateNOX,which in 2008 synergise withangiotensinIItodoso( via EGFRtoincreaseNOXgenerationofROS,andcan 2005 regulation ofNOX( a non-genomicmineralocorticoidcontributionto transcription andproteinsynthesis,stronglysupport NOX generationofROS,despitetheinhibition 2010 and cardiomyocytes( NOX within minutes in VSMCs ( ( induced cardiovascularoxidativestressandinflammation suggests specificisoformsareresponsibleforRAAS- in hearttissuewhereasNOX1andNOX4arenot.This experimental RAASoveractivation,NOX2isupregulated Queisser cardiomyocytes ( that thisprocessisdistincttoseeninVSMCsand over 6 However, thereisamuchslowerincreaseinNOXactivity ( increases p47phoxlocalisationtothecellmembrane 2002 assembly ofothersubunitsintoactiveNOX( the NOXcytosolicsubunitp47phox,whichallows ( GTP-bound RAC1withoutincreasingproteinlevels at leastinendothelialcells.Here,activatedMRincreases Cannavo 2005 one studyusingHL-1atrialcardiomyocytesfoundno effect isMRdependentinmoststudies( through theAP-1andNF- of proinflammatory, profibroticandangiogenicgenes MR activationofNOXisc-Src-dependent ( effect of spironolactone( inhibitory Mineralocorticoid cellsignalling Stas Keidar Iwashima Published byBioscientifica Ltd. Additionally, MR upregulatesNOXbygenomicmeans: Aldosterone rapidlyincreasesROSgenerationby a ). Incardiomyocytes,theMR-EGFRinteraction , ). Therapidonsetofactionandpersistence ). Supplementing this process, MR activation also , et al , Hayashi

h byaldosteroneinendothelialcellssuggesting Iwashima Nagata et al et al . 2007 et al et al . 2004 Cannavo . 2011 . 2016 et al et al . 2008 , Nakamura Iwashima , t al et . 2006 . 2008 Miyata ), withdownstreamactivationofRAC1 ). ManysubtypesofNOXexist,butin Hayashi ). RAC1generatesROSbyactivating et al . 2008 Hayashi , Downloaded fromBioscientifica.com at09/27/202102:29:00PM , κ Stas . 2016 Iwashima et al B pathways( Nolly et al t al et et al et al , . 2005 . 2009 ). Montezano . 2008 t al et . 2008 . 2007 t al et et al a Callera , . 2008 ). 58

. 2014 Nagata Fiebeler ). MRalsosignals Tsai ). Thealdosterone ). MAPK signalling . 2008 : Montezano 1 Callera t al et Callera , t al et Miyata t al et ). TheMR– Babior et al ), although Tsai et al . 2010 . 2005 . 2008 . 2006 . 2001 R40 t al et t al et t al et et al et al et al via freeaccess ). ). ) . . . , . . . , Review g s y ong and m j young Mineralocorticoid cell signalling 58:1 R41

apoptosis signal-regulating kinase 1 (ASK1), a MAPK kinase mammary glands (Quirk et al. 1983), where it regulates kinase, attenuates aldosterone-induced cardiac NOX2 cellular electrolyte handling. MR activation leads to upregulation, superoxide generation and cardiac fibrosis both rapid and sustained homeostatic effects through (Nakamura et al. 2009). AGTR1 signalling is required for a combination of second messenger signalling and MR-mediated Ncf1 transcription (the p47phox gene) in early and later transcribed genes, which have been best rat aorta, but not for other subunits (Hirono et al. 2007). characterised in the renal epithelial cell. This is illustrated This latter effect is in parallel to the AGTR1 synergy with in Fig. 2, and described in detail in the following sections. MR in EGFR/PI3K signalling in cardiomyocytes discussed MR regulation of target genes is the most potent previously (Montezano et al. 2008). determinant of its life-sustaining effects (Fig. 2, sections Cellular redox status influences many of the cellular B and C). MR-knockout mice suffer early demise due processes triggered by MR activation and even the to dehydration and salt wasting despite compensatory method of MR activation itself (Fig. 1, sections B and elevation in the components of the RAAS (Berger et al. C). For instance, ligand-free MR activation enabled in 1998). This fate is shared by mice homozygous for a oxidative stress may partially explain the benefits to non-synonymous substitution in the MR DBD, which cardiac infarct healing with spironolactone treatment of abolishes its ability to bind to DNA and regulate primary adrenalectomised rats, despite the absence of endogenous gene transcription (Cole et al. 2015). Hence, MR regulation ligands to activate the MR (Mihailidou et al. 2009). The of target genes is critical for this function. Examples of generation of ROS is a necessary co-factor for certain MR the effect of MR target genes are well described in renal signalling pathways; for example, antioxidant treatment physiology. All distal nephron epithelial cells express attenuates the ability of aldosterone to transactivate the ENaC, which is the major contributor to resorption EGFR (Huang et al. 2009) and IGF1R (Cascella et al. 2010). of sodium in the distal nephron (Kellenberger & Schild Also, some MR-mediated transcription could be redox 2002). ENaC is a heterotrimeric protein comprised of α-, sensitive including SGK1, SLC9A1 (encoding for NHE-1), β- and γ-subunits, which undergo intracellular processing and some pro-inflammatory and profibrotic genes before export via vesicles to the apical membrane where (Callera et al. 2005, Pinto et al. 2008, Nakamura et al. it becomes active (Eladari et al. 2012). MR activation 2009). The specific mechanisms of ROS contribution to increases sodium influx via ENaC, partially through direct MR function and maladaptive organ remodelling and transcription of the α-subunit (Scnn1A) (Masilamani et al. damage will be described in the next section. 1999, Mick et al. 2001). MR activation also increases total protein levels of the Na/K-ATPase pump within 24 h,

Journal of Molecular Endocrinology which is responsible for exporting sodium out of the Examples of coordinated MR transcriptional basolateral cell membrane to the interstitium (Alvarez de and rapid signalling effects in homeostasis la Rosa et al. 2006). and disease MR also increases the expression of genes that Although most of the cell signalling systems activated regulate post-translational modifications of the electrolyte by MR and mineralocorticoids are ubiquitous, a uniform handling machinery, providing a more rapid response coordinated response is observed within specific tissues. than direct synthesis of channels or transporters (Fig. 2, While this has been best characterised in renal tubular section B). SGK1 is one such rapidly transcribed gene, epithelial cells, there is expanding knowledge of the which increases activity of ENaC (Chen et al. 1999). It also mechanisms of MR effect in the cardiovascular system increases thiazide-sensitive sodium chloride cotransporter and immune cells. In this section, the interaction between (NCC) activity (Faresse et al. 2012, Ko et al. 2013), aldosterone, MR, second messenger systems, receptor which is a lesser contributor to renal sodium resorption transactivation and gene transcription will be illustrated (Gamba et al. 1994). The early effects of SGK1 are largely to in the context of organ function or disease. preserve the active surface expression of ENaC and NCC. SGK1 phosphorylates the ubiquitin protein ligase Nedd4- 2, preventing it from tagging ENaC or NCC for destruction Renal sodium handling (Snyder et al. 2002, Arroyo et al. 2011). SGK1 also directly The MR is expressed in epithelial cells, most importantly interacts with the SCNN1A to increase the proportion of in the distal nephron (Doucet & Katz 1981, Farman et al. active open ENaC channels (Diakov & Korbmacher 2004), 1982), but also in sweat glands (Kenouch et al. 1994), and promotes ENaC transcription (Zhang et al. 2007). With the gastrointestinal tract (Rafestin-Oblin et al. 1984) and similar enhancing effects on NCC (Rozansky et al. 2009,

Holzman s

SGK1 ong Collins . 2012 et al and ). This generates Printed inGreatBritain ) contributeto whichcodesfortheENaCchannel Oberfeld . 2006 min, forming ) andGILZ1 t al et m et al

young . 2007 . 2003 ), SGK1 i. 2 Fig. t al et min ). ). , . 2013 effect onENaCtransport( export ofENaCsubunits,and enhancesthedirectPKD1 (PI4KIIIb) inthetrans-golgi network,whichpromotes complexes withphosphatidylinositol 4-kinaseIIIb For example,aldosteroneinducesPKD1torapidlyform second messengerscanresultinopposingcellulareffects. 2004 ( towards, andinsertinto,theapicalcellularmembrane golgi networkinendosomes.Eventuallythesearedirected in theGolgiapparatus,emergingfromadjacenttrans- Dooley in factisanegativeregulatorofENaC( via RAF-MEK-ERK1/2( ENaC activity inaPI3K-dependent manner rather than activating thoseofanother. Forexample,K-RAS upregulates in isolation,withcomponentsofsomepathwayscapable of PKD1 ( with thisredistribution,whichcannotoccurwithout of ENaCinducedbyaldosteroneafter2–4 cell membranewithin30 and ENaC subunit translocation from cytoplasm to trafficking ofENaCsubunitsisenhancedwithin2 Mineralocorticoid cellsignalling SGK1 Butterworth 2010 Butterworth Published byBioscientifica Ltd. Second messenger systems activated by MR do not act Second messengersystemsactivatedbyMRdonotact , ). However, PKD1alsoprolongsMR-induced ERK1/2 ). Occasionally,). interactionsbetween downstream CNKSR3 McEneaney et al α -subunit. Incombination,theMRcanprovidearapidand and . 2013 GILZ ). ENaCsubunitsareinitiallypackaged ). TheMR-dependentincreasedactivity ) whichenhanceENaCactivityandprevent et al . 2008 Staruschenko Downloaded fromBioscientifica.com at09/27/202102:29:00PM Hausser min ( , 2010 McEneaney et al b , t al et Dooley . 2005 58 Grossmann : 1 . 2004 h iscorrelated , Dooley t al et et al ), which ), which . 2013 . 2008 R42 et al. et al. et al min via freeaccess ). . , Review g s y ong and m j young Mineralocorticoid cell signalling 58:1 R43

activation (McEneaney et al. 2010a), which increases rapidly signals via PI3K/Akt to increase eNOS production degradation of ENaC via PKC, to mitigate the effect of of NO within 2 minutes (Liu et al. 2003, Mutoh et al. increased ENaC expression (Booth & Stockand 2003). 2008). However, MR activation reduces eNOS activity in HUVECs (Hashikabe et al. 2006). Rapid induction of RhoA kinase activity by MR maximally reduces eNOS activity Vasomotor and endothelial function within 15 min by inhibition of Akt (Kirsch et al. 2013), Vascular endothelial cells and VSMCs express the MR while prolonged MR activation (16 h) also inhibits eNOS (Lombes et al. 1992), with MR signalling in these tissues activity by increasing protein phosphatase 2A activity, contributing to regulation of vasomotor tone. However, which dephosphorylates eNOS (Nagata et al. 2006). As MR the literature varies on if, and under what context, acts through different pathways with opposing outcomes, mineralocorticoids exert a constricting or relaxing effect, context is important in determining its effect on eNOS. and whether that action is direct or via augmentation of Vascular endothelial MR genomic effects increase responses to other vasoactive stimuli. A summary of MR oxidative stress. The NOX subunit p47phox has increased signalling in vascular function is presented in Fig. 3. expression and membrane localisation in response to MR Endothelial MR influences NO levels, which impacts activation, with ROS generation after 2 h (Nagata et al. on vascular tone (Fig. 3, top section). NO is generated by 2006). Additionally, aortic expression of cyclooxygenase eNOS, which diffuses into adjacent VSMCs, and triggers (COX)-2 is increased in aldosterone-treated rats (Blanco- generation of cyclic guanosine monophosphate (cGMP) Rivero et al. 2005, Eatman et al. 2011). COX-2 generates which ultimately results in relaxation (Förstermann & vasoactive prostanoids and ROS (Félétou et al. 2011), Münzel 2006). In bovine aortic endothelial cells, MR which impairs vasodilatory (Blanco-Rivero et al. 2005) and Journal of Molecular Endocrinology

Figure 3 Mineralocorticoid mediated genomic (left) and non-genomic (right) events in the control of vascular function. In both endothelial (top section) and vascular smooth muscle cells (VSMCs), the PI3K pathway is an important second messenger system through which MR activates endothelial nitric oxide synthase (eNOS) and VSMC contractile elements such as myosin light chain (MLC). In VSMC, the presence of GPER enhances the effect through unknown mechanisms. Rapid effects on the ENaC sodium channel and sodium/hydrogen exchanger (NHE-1) are pro-constrictive. In VSMC, rapid increases to cAMP leads to upregulation of the CREB transcription factor, linking rapid signalling and genomic transcription. Genomic effects in endothelium includes increased synthesis of protein phosphatase 2A (PP2A) which deactivates eNOS, and NADPH oxidase (NOX) and cyclooxygenase (COX) which generate

reactive oxygen species (ROS) impairing eNOS function. In VSMC, the MR can upregulate Cav1.2, an L-type voltage dependent calcium channel. The balance between different MR effects and other in vivo mediators determines overall vasomotor tone.

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-15-0318 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 02:29:00PM via free access Journal of Molecular Endocrinology picomolar tonanomolarconcentrations ofaldosterone, endothelial cells,eNOSactivity ismaximallyactivatedby arterioles ( of angiotensin II exposure in mesenteric but not coronary responsivenessafter2 weeks NO-dependent vasodilatory example, endothelialcell-specificMRdeletionimproved duration of exposure, and environmental context. For differences includeanatomicalsite,steroiddoseand of experimentalconditionsintheliterature.These framework,butthereisalso heterogeneity regulatory reduce vascularreactivityandtonesuggestingacomplex volume andstiffness( early( blocks allbutthevery to shear stress ( exposure, which stiffens the cell and renders it susceptible macromolecules occurswithprolongedaldosterone Later, MR-mediated synthesis of cytosol-crowding 2003 ( effect. Aldosterone-inducedrapidactivationofNHE-1 and tensionareincreasedbyaldosteronewithdeleterious effects onvasomotorfunction.Endothelialcellvolume ( healing inresponsetoinjury and oxidative stress correlates with impaired endothelial Nagata endothelial NOproduction( a contributingmechanismforMR-mediatedreductionin causing productionofmoreROSinsteadNO,andis generation by eNOS. Depletionof BH4 uncouples eNOS, (BH4), apotentreducingagentandco-factorforNO also contributestodepletionoftetrahydro- prevents itsstimulationofeNOS( oxidative modificationofendothelin-Breceptor, which can compoundadverseeventssuchastheinactivating 2007 generation andNO-dependentvasodilation( which worsensoxidativestressandimpairsbothNO glucose-6-phosphate dehydrogenase(G6PD)expression, cardiac COX-2upregulationinrats.MRactivationreduces 2002 eplerenone mitigatedbothangiotensinII( were MRmediated,althoughintwodifferentstudies, not specificallyinvestigateifthesealdosteroneeffects ( the femoralartery and renal arteries,whereas it induces downregulation in uniform; itinducesupregulationofCOX-2intheaorta The effectofaldosteroneonCOX-2expressionisnot enhances vasoconstrictiveresponses( Schneider DOI: 10.1530/JME-15-0318 http://jme.endocrinology-journals.org Review Activation of the endothelial MR canbothincrease and Aldosterone and MR alsoexertNO-independent ) contributestoswelling,whichistransient. ). ThisenvironmentofMR-mediatedoxidativestress a ) andaldosterone( et al Mueller . 2006 t al et Oberleithner . 1997 , Chen Eatman t al et Oberleithner ) and/orENaC( et al . 2015 Rocha et al Förstermann &Münzel2006 . 2016 et al Chen ). Also,inbovineaortic . 2011 < g . 2006

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) induced -biopterin young . 2011 t al et t al et et al ). It ). . . . , genomic effectscanbevasoconstrictive( renal arteriolespromotevasodilation,delayed-onset Furthermore, whileearlyrapidMReffectsinafferent with diminishedeffectathigherconcentrations( replicate thecomplex and AGTR1 effectinthelatterstudy. ( for aldosterone-mediatedendothelialdysfunction ( arteries inanMAPK-andNO-independentmechanism II-induced vasoconstrictioninhumancoronary rat aorta( tendencyin in anendothelium-dependentvasodilatory other receptors. Aldosterone activation of GPER results 2003 than micromolarconcentrations( microarteries, maximaleNOSactivationrequiredhigher 2003 sodium isexacerbatedbyan earlytransientMR-induced, Carreno prolonged MR-dependentresponse ( manner: arapidMR-independent mechanismanda influx areincreasedby aldosteroneinabiphasic mineralocorticoid control.NHE-1activityandsodium genomic transcription( factor CREBwithin10 levels within1 an MR-independentmechanismtoincreaseVSMCcAMP active ( calcium channelwhichincreasesvasomotortonewhen VSMC, anL-type gene expressioninmesentericartery ( signalling systemsisunaffectedbyMRdeletioninVSMC of genescodingforcontractileelements,ionchannelsor PI3K signalling( 2014 enabling actin–myosincoupling( stepin ofMLCbyMLCKisanecessary phosphorylation myosin lightchain(MLC)2( regulators myosinlightchainkinase(MLCK)and with reductioninbaselineactivationofthecontractile cGMP- andcalcium-dependentsignallingisimpaired responses ( maintaining basaltoneandvascularcontractile purpose thanseenacrossindividualexperiments. related inputs,whichtogethergeneratemoreunityof interacting autonomic,endocrine,paracrineandstress Mineralocorticoid cellsignalling Tarjus Briet Batenburg Published byBioscientifica Ltd. Sodium handlinginVSMCsisunder In theVSMC,MRsignallingisimportantfor ex ) andoccurswithin15 ). Theheterogeneityextendstosignallingthrough , et al Leopold

McCurley vivo t al et et al Gros . 2016 isolatedvesselexperimentalsystemscannot et al i. 3 Fig. . 2015 . 2015 et al . 2012 et al min, whichactivatesthetranscription ), thisdiscordancemayreflectaspecific Gros et al , bottomsection).IfMRisdeleted, a . 2007 ). However, MR does regulate Ca . 2013 ). Theresultantriseinintracellular ). AsAGTR1asignallingisimportant . 2012 et al min, linkingrapidsignallingwith in vivo Christ Downloaded fromBioscientifica.com at09/27/202102:29:00PM ). However, inhumancoronary ), butpotentiatesangiotensin- . 2011 ). Aldosteronecanalsoactin milieuofchangeableand min ofMRactivationvia et al Tarjus a ). Thebasalexpression . 1999 Batenburg Goulopoulou &Webb In vitro Miyata 58 t al et : ). 1 Uhrenholt . 2015 cellculture et al et al Liu . 2005 . 2012 a ). The R44 et al et al v 1.2 via freeaccess b ). ). , . . Review g s y ong and m j young Mineralocorticoid cell signalling 58:1 R45

PKC-dependent reduction in VSMC Na/K-ATPase surface of action potentials. MR activation increases calcium activity and expression (Alzamora et al. 2003). However, current through both L-type and T-type calcium with sustained MR activation and sodium influx, there is channels (Lalevee et al. 2005, Boixel et al. 2006). The increased Na/K-ATPase subunit transcription (Muto et al. calcium status of cardiomyocytes is strongly linked to 1996). These changes affect cellular membrane potentials transmembrane sodium concentrations (Bogeholz et al. and calcium handling, with potential consequences 2012, Aronsen et al. 2013). Aldosterone raises intracellular on VSMC function (MR-mediated NHE-1 activity sodium levels by rapidly promoting sodium influx contributes to vasoconstrictive responses in the aorta) through the NHE-1 (Korichneva et al. 1995, Matsui et al. (Carreno et al. 2015). 2007) within 10 min via MR transactivation of EGFR (De Functionally, VSMC MR generally promotes a Giusti et al. 2011), the electrogenic sodium/bicarbonate contractile response, augmenting the constrictor effect cotransporter (SLC4A4) via GPER and PI3K/Akt (De of thromboxane-A2 and angiotensin II in aged animals Giusti et al. 2015, Orlowski et al. 2016), and the Na-K-2Cl (Gros et al. 2011a, McCurley et al. 2012). VSMC MR has cotransporter (SLC12A) via a PKCε-dependent pathway a role in hypertension, with VSMC MR knockout mice (Mihailidou et al. 1998, 2004). This PKCε pathway having lower basal blood pressures (Galmiche et al. 2014) also mediates a reduction in Na/K-ATPase activity, and protection against age-related increases to systolic inhibiting sodium export (Mihailidou et al. 2000, 2004). blood pressure (McCurley et al. 2012). However, MR also While SLC12A activity continues with prolonged MR is important for NO-mediated relaxation of VSMC, and signalling, the Na/K-ATPase inhibition is only transient increases cAMP that has a vasodilatory effect, which (Mihailidou et al. 2004). may be autoregulatory in the presence of functional As a regulator of intracellular pH and cell volume endothelium (Christ et al. 1999, Tarjus et al. 2015a). through the exchange of sodium for hydrogen, NHE-1-dependent cellular alkalinisation can increase myofilament responsiveness to calcium Mattiazzi( 1997) The cardiac action potential, excitation–contraction and may explain aldosterone’s rapid inotropic effect on coupling and electrical remodelling cardiomyocytes (Barbato et al. 2002, 2004). NHE-1 is also The identification of MR expression in human important in generating a stretch-induced secondary cardiomyocytes indicates that MR exerts direct effects slow force contractile reaction that occurs after the on the heart (Bonvalet et al. 1995, Lombes et al. 1995). initial Frank–Starling response. It is postulated that an Cardiomyocyte contraction is critically dependent angiotensin-II-mediated local generation of aldosterone

Journal of Molecular Endocrinology upon intracellular calcium, which binds to troponin-C, acts via EGFR, with downstream ROS generation and unleashing a cascade of events that eventually ERK1/2 phosphorylation activating NHE-1 to trigger facilitate actin and myosin filament movement and contraction. MR knockdown with hairpin interfering sarcomere contraction. Calcium influx and release RNA blocks the slow force response, with reduced from the sarcoplasmic reticulum is triggered by ERK1/2 phosphorylation and NHE-1 activity (Diaz et al. electrical depolarisation of the vesicle membrane. Atrial 2014). Although this hypothesis is controversial due and ventricular cardiomyocytes are prone to rapid to difficulty in identifying aldosterone synthase in the depolarisation, with their electrical status determined by heart (Ye et al. 2005), increased aldosterone synthase the actions of sodium, calcium and potassium channels. gene expression in heart failure patients (Yoshimura et al. Voltage-gated calcium channels are important for coupling 2002) and the persistence of aldosterone in the hearts depolarisation to contraction, by facilitating calcium of adrenalectomised rats (Gomez-Sanchez et al. 2004) influx into the cell and triggering the release of calcium suggest some cardiac capacity for aldosterone generation from the sarcoplasmic reticulum (Lipscombe 2002). in response to major disturbances to normal function. MR activity can thus modulate cardiomyocyte electrolyte There is the possibility that MR can mediate electrical handling, the action potential and cardiac contractility. dysfunction. Cardiac-specific overexpression of MR in Cardiomyocytes express both low-voltage-activated mice leads to an increase in action potential duration and T-type channels which exhibit rapid activation and ventricular arrhythmia due to aberrant release of calcium slow deactivation, and L-type dihydropyridine channels from the sarcoplasmic reticulum (Ouvrard-Pascaud et al. which activate more slowly but deactivate more rapidly 2005, Gomez et al. 2009). In humans, PA patients are than T-type channels (Lipscombe 2002). Both are also at higher risk of atrial fibrillation (AF) compared to age important for pacemaker activity and propagation and blood pressure matched controls (Milliez et al. 2005,

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-15-0318 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 02:29:00PM via free access Journal of Molecular Endocrinology eiaclradcricifamto ihn1 days perivascular andcardiacinflammation within14 or hypertension. pathology extendsmorebroadly thanhyperaldosteronism multiple mechanisms,andthecontributionofMR to through from injury influences cardiovascularrecovery ( potential forRAC1-inducedligand-freeMRactivation MI after adrenalectomy ( protection fromspironolactoneinananimalmodel of for MR-mediatedadverseoutcomes,withongoing presence of endogenous ligands may not be required than mineralocorticoidactivationofMR.However, the benefits maybeduetoinhibitionofglucocorticoidrather antagonists suchasspironolactoneandeplerenone.These cell-specific MRknockdown/deletion, oruseofMR and/or diastolic function is attenuated through either 2007 ( valvular incompetence( 2010 2011 of cardiacdamagefrompressureoverload( myocardial infarction ( mineralocorticoid excess, suchasheartfailureafter MR antagonistsareusedindiseasestatesunrelatedto hypertension patients( (‘essential’) to that experienced by treated primary Treatment reducestheriskofsignificantCVDevents hypertension ( infarction (MI), beyond that attributable solely to disease (CVD)events,suchasstrokeandmyocardial with PA haveincreasedriskofsignificantcardiovascular 2013 cardiac leftventricularhypertrophy( with hypertensionandendorgandisease,including persistent excessivesecretionofaldosteroneisassociated with adversecardiovascularoutcomes,asseeninPA. The Chronic excessive MR activation is uniformly associated Cardiovascular inflammation,fibrosis and repair 2005 mechanism for arrhythmia pathogenesis ( MR-mediated structuralremodellingsuggestingadual and downregulationofpotassiumchannels,precedes remodelling, suchasupregulationofcalciumchannels Catena Nagase Delyani DOI: 10.1530/JME-15-0318 http://jme.endocrinology-journals.org Review Persistent MRoveractivation isassociatedwith Curiously, thereisclinicalevidenceofbenefitwhen ). Cardiacremodellingwithimpairmenttosystolic , , ) andrenalimpairment( , Ouvrard-Pascaud Bienvenu Li t al et t al et t al et t al et 2012 . . 2001 . 2008 Milliez . 2014 t al et ). ThissuggeststhatMRsignalling , , Enomoto . 2012 t al et ), oxidativestress( Pitt Catena et al Savard Mihailidou Zendaoui . 2005 et al . 2005 , Coelho-Filho Sechi et al . 2003 t al et t al et g ,

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). Patients ) andMI young ) and the . 2014 . 2013 . 1996 t al et t al et t al et t al et ). ), , . . . . CCR5 andP-selectin( this includesintercellular adhesionmolecule(ICAM1), recruitment, adhesionandinfiltration.Inendothelialcells, after upregulationoffactorsthatenhanceleucocyte of constantmineralocorticoidexposure( cytokines such as TNF- Myeloid cells increase the generation of pro-inflammatory cells. and influencingthebehaviourofinflammatory Once recruited,MRsignallingisimportantforactivating and osteopontinviaERKp38MAPK( via PDGFR and c-Src activation ( molecule-1 (VCAM1)proteinexpressionupregulation and adhesion,withICAM1vascularcelladhesion regulate transcriptionofgenesinvolvedinrecruitment (VEGF) receptor( monocytes viaFLT1, avascularendothelialgrowthfactor growth factor production in VSMC, which recruits 2009 2002 chemoattractant factors,are subjecttoindirectMR pro-hypertrophic andprofibrotic and,similarto enhancer factor2(MEF2)( (CAMK2), whichdrivesMmp9transcriptionbymyocyte oxidises calcium/calmodulin-dependentproteinkinase II MMP9 generation( are prerequisitesforMR-mediatedERKactivationand cardiomyocytes, PKCandthegenerationofROSbyNOX PI3K, p38 MAPK and ERK signalling ( infiltration. Inneutrophils,increasedtranscriptionof cell messenger pathways,enhancinginflammatory upregulates MMPproductionutilisingvarioussecond into activeforms( cytokines and cleaveprecursorsofpro-inflammatory SGK1 ( the regulationofNF- aldosterone ( via JNK/AP-1 and ERK cascades ( MMP12 productionrequiresintact MR signalling Gilet MMP9 ( phenotype polarise macrophagestoananti-inflammatory profile issimilartothatinducedbyIL-4,whichknown profile inresponsetoMRantagonisttreatment.This an anti-inflammatory, pro-healinggenetictranscription blood monocytesofhealthyhumanvolunteersdeveloped 2012 Mineralocorticoid cellsignalling Labuzek Published byBioscientifica Ltd. A number of MR-regulated genes are mitogenic, Matrix metalloproteinases (MMPs) degrade collagen , b ). Conversely, macrophagesderivedfromperipheral et al , andpro-angiogenic Rickard Zhang Usher et al . 2015 Usher . 2013 et al t al et t al et ). Inmyeloidcells,suchasmacrophages, McGraw . 2010 Schonbeck . 2005 Rude ). et al . 2014 κ B, whoseactivityisenhancedby Caprio α . 2010 et al , Downloaded fromBioscientifica.com at09/27/202102:29:00PM , IL-1b and IL-6 in response to , Rickard ). Also,MRinducesplacental He et al Leroy VEGFA . 2005 et al ). Manyoftheseareunder et al . 2013 t al et t al et . 2011 et al ). TheMR-inducedROS byMRrequiresintact . 1998 Shen Callera . 2008 ). MRcanindirectly Walczak 58 . 2009 . 2012 ). : 1 ). MRactivation t al et Fu , t al et Rocha , ). Thisarises Jeong et al . 2016 Ding et al . 2011 . 2012 . 2011 R46 t al et t al et t al et ). In a via freeaccess ). ), . . , .

Review g s y ong and m j young Mineralocorticoid cell signalling 58:1 R47

regulation using second messenger systems. For increased transcription of culprit genes. As MR activation example, MR acts through ERK signalling to induce simultaneously promotes production of ROS, particularly cardiac fibroblast proliferation (Stockand & Meszaros through NOX2, a self-sustaining interaction could 2003) and cardiomyocyte transcription of hypertrophy- exacerbate and potentiate inflammation and fibrosis. MR associated proteins such as α- and β-myosin heavy chain is important for the transcription of NOX and its p22phox (Okoshi et al. 2004). Additionally, MR signalling via p38 subunit (Fiore et al. 2009). In the heart, this appears to MAPK promotes cardiomyocyte production of connective be driven by infiltrating macrophages, as prevention of tissue growth factor (CTGF), which is a profibrotic their recruitment reduces NOX upregulation and cardiac stimulus (Lee et al. 2004). Transactivation of other fibrosis Rickard ( et al. 2012, Shen et al. 2014). Aldosterone receptor systems is involved in MR-mediated remodelling. acts via MAPK to increase NOX2, CCL2 and TGF-β1 AGTR1 transactivation is required for the upregulation expression and to cause cardiac fibrosis Nakamura ( et al. of fibrotic and hypertrophic genes such as transforming 2009). NOX-generated ROS also contributes to vascular growth factor-beta (TGF-β), Col1a, Col3a and Acta2 (which remodelling. MR-induced IGF1R expression, activation encodes α-smooth muscle actin) in cardiomyocytes via and downstream signalling (via MAPK and PI3K/Akt) ERK and JNK (Tsai et al. 2013), while the pro-hypertrophic with subsequent VSMC cell proliferation and migration MEF2 requires AGTR1 signalling via the G-protein are ROS dependent (Cascella et al. 2010). Similarly, the coupled receptor kinase (GRK) 5 (Cannavo et al. 2016). reparative function of endothelial progenitor cells from In cardiac fibroblasts, aldosterone acts via an unknown PA patients is impaired by eNOS uncoupling related to membrane G-protein coupled receptor (and not MR) to increased NOX production of ROS (Chen et al. 2016). transactivate IGF1R via c-Src, with downstream PI3K/Akt Therefore, redox status determines the outcome of several signalling leading to elastin production (Bunda et al. MR-mediated pathological processes. 2009). EGFR transactivation by cardiac MR increases NHE-1 activity (Fujisawa et al. 2003, Young & Funder 2003, De Giusti et al. 2011) with resultant sodium accumulation Conclusions promoting calcium influx and activation of MAPK (p38, So far, the uncovered mechanisms of action of ERK), Akt, calcineurin and CAMK2. This facilitates the mineralocorticoids and the MR paint a picture of a generation of pro-hypertrophic factors (Darmellah et al. sophisticated multifunctional system. Harnessing cellular 2007, Nakamura et al. 2008). EGFR transactivation may second messenger systems while genomic transcription be profibrotic, as it is mitogenic in a renal fibroblast cell events are given sufficient time to increase and sustain Journal of Molecular Endocrinology line via JNK, ERK and PI3K/Akt cascades (Huang et al. its defence against hypovolaemia, MR activation in the 2012). However, in vivo impact on fibrosis may be limited, kidney and vessels shows itself to be an agile and powerful with impaired EGFR function not protecting mice preserver of homeostasis. Yet, MR activation and triggering against mineralocorticoid-induced cardiac remodelling of the same genes and signalling pathways elsewhere and (Messaoudi et al. 2012). Several profibrotic genes are under different circumstances can lead to recruitment of directly regulated by MR as a transcription factor. As inflammatory cells and fibrosis or maladaptive repair in in the kidney, MR increases SGK1 transcription in the response to injury. There is an increasing body of work heart (Martin-Fernandez et al. 2011). SGK1 upregulates regarding the contribution of various MR expressing cell the profibrotic CTGF Vallon ( et al. 2006, Terada et al. types to tissue inflammation, fibrosis, maladaptation 2012), and the importance of SGK1 in the pathogenesis and hypertension, but there is a concurrent need to map of MR-mediated cardiac fibrosis has been established in the gene targets and intracellular signalling pathways a knockout mouse model (Vallon et al. 2006). Neutrophil underlying these outcomes. Eventually, this could gelatinase-associated lipocalin (Lcn2) is a directly lead to novel therapeutic options such as targeting MR-regulated gene in cardiomyocytes (Latouche et al. transactivated receptors and superoxide generation in 2012). LCN2 is a stimulus for fibroblasts to deposit type 1 combination with MR antagonism. There is also scope for collagen and plays a pathological role in MR-mediated development of new agents that preferentially obstruct coronary perivascular fibrosis Tarjus ( et al. 2015b). pathological signalling whilst preserving the essential Oxidative stress is a key facilitator of adverse electrolyte regulatory effects of MR. remodelling and inflammatory effects of the MR There are many unresolved issues in including rapid effects on vascular function and the mineralocorticoid and MR signalling. It is likely that

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-15-0318 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 02:29:00PM via free access Journal of Molecular Endocrinology Aronsen JM, Swift F & Sejersted OM 2013Cardiacsodiumtransportand &Sejersted OM Swift F Aronsen JM, 2003Nongenomic &Michea L Marusic ET, Gonzalez M Alzamora R, 2006SGK1 &Canessa CM Forbush B laRosaD,Gimenez I, Alvarez de Habermehl D, Loffing-Cueni D, Carrel M, Gresko N, Ackermann D, 2008RoleofIGF-1inglucose &Kearney MT Grant PJ Abbas A, References editing ofthemanuscript. The authorswouldliketothankDrJunYang forcriticalappraisaland Acknowledgements Government’s OperationalInfrastructureSupportProgram. Award scholarship.TheHudsonInstituteissupportedbytheVictorian G OissupportedbytheAustralianGovernment’s AustralianPostgraduate Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest behind themultifunctionalMR. will emerge,leadingusclosertotheintelligentdesign between studies.Instead,wehopethatclearerpatterns and variationsinmechanismsfunctionaloutcomes expands, there is a risk of confusion from inconsistencies inputs in which cannotaccountforthenumerouscontributing vitro in current research methodsinthisarealargelyrelyon including theelusivemembraneboundMR.However, incomplete, andothercandidatereceptorsmayexist mechanism ofMRinteractionwithGPERitselfis is increasingevidencethatGPERinvolved.The without bindingtoitsclassicalMR,althoughthere through whichmineralocorticoidscaninduceeffects there ismoretodiscoveraboutthemembranereceptors or context-dependent ligand-free activation. Similarly, specific activationbyitsseveralhigh-affinityligands additional mechanisms protect the MR against non- DOI: 10.1530/JME-15-0318 http://jme.endocrinology-journals.org Review Cardiology excitation-contraction coupling. vessels. effect ofaldosteroneonNa+,K+-adenosine triphosphataseinarterial ajpcell.00556.2004) ofPhysiology:CellPhysiology Journal activates Na+-K+-ATPase inamphibianrenalepithelialcells. F1473–F1485. tubule. rat kidney:differentialeffectofcorticosteroidsalongthedistal translocation ofmineralocorticoidandglucocorticoidreceptorsin 2010Invivonuclear &Loffing J Rossier BC Gomez-Sanchez C, Therapy regulation andcardiovasculardisease. and

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http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-15-0318 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 02:29:00PM via free access Journal of Molecular Endocrinology Félétou M, Huang Y & Vanhoutte PM 2011Endothelium-mediated &Vanhoutte PM Huang Y Félétou M, 2015 Copernicusrevisited:overturning &Limbird LE Feldman RD 1982Aldosteronebindingin &Bonvalet JP Vandewalle A Farman N, Fejes- Maillard M, Ismailji A, Debonneville A, Lagnaz D, Faresse N, Yoshiyama M, Kusuyama T, Omura T, Kim S, Enomoto S, Matsumoto R, 2012Anewlookatelectrolyte &Peti-Peterdi J Chambrey R Eladari D, 1963Onthemechanismofaction &Porter GA Bogoroch R Edelman IS, 2011 &Bayorh MA Watson J, Rollins-Hairston A Peagler K, Eatman D, 1981Mineralcorticoidreceptorsalongthenephron: &Katz AI Doucet A 2013 &Harvey BJ Yusef YR, Thomas W Angibaud E, Dooley R, 2012Chronicinhibitionofnuclear Ding W, &Gu Y Yang L, Zhang M Nolly MB, Caldiz CI, Villa-Abrille MC, Morgan PE, Perez NG, Diaz RG, Diakov A & Korbmacher C 2004Anovelpathwayofepithelialsodium &Korbmacher C Diakov A 2001Effectofaselective &Rudolph AE Robinson EL Delyani JA, Caldiz CI, Gonano LA, Espejo MS, Ciancio MC, Orlowski A, De Giusti VC, Chiappe Villa-Abrille MC, Yeves AM, Caldiz CI, Nolly MB, De Giusti VC, DOI: 10.1530/JME-15-0318 http://jme.endocrinology-journals.org Review control ofvasculartone:COX-1and COX-2products. Metabolism Ptolemy’s viewoftheGPERuniverse. parts oftherabbitnephron. isolated tubulesI.Biochemicaldeterminationinproximalanddistal ajprenal.00535.2011) of Physiology:RenalPhysiology Sgk1 knockoutmiceshowasalt-losingphenotype. 2012Induciblekidney-specific Toth G, Naray-Fejes-Toth A &Staub O 1595–1600. to cardiacremodellingaftermyocardialinfarction. eplerenone ontranscriptionalfactorsandmRNAexpressionrelated Takeuchi K, Iwao H, Izumi Y, Akioka K, 325–349. transport inthedistaltubule. PNAS of aldosteroneonsodiumtransport:theroleproteinsynthesis. 0500-4-125) aorta byaldosterone. The involvementofprostaglandinsinthecontractilefunction Physiology [3H]aldosterone bindinginrabbittubules. Endocrinology signalling inM1corticalcollectingductcells. protein kinaseD1-phosphatidylinositol4-kinaseIIIbetatransGolgi Aldosterone-induced ENaCandbasalNa+/K+-ATPase traffickingvia Science factor kappaBattenuatesaldosterone/salt-inducedrenalinjury. HYPERTENSIONAHA.113.01726) functional consequences. mineralocorticoid receptoractivationbystretchingandits 2014Myocardial &Cingolani HE Ennis IL Portiansky EL, (doi:10.1074/jbc.M403260200) subunit. kinase consensusmotifintheCterminusofchannel’s alpha- channel activationinvolvesaserum-andglucocorticoid-inducible andCirculatory Physiology ofPhysiology:Heart Journal aldosterone receptorantagonistinmyocardialinfarction. Cellular Cardiology of thegprotein-coupledreceptorgpr30. stimulates thecardiacsodium/bicarbonatecotransporterviaactivation 2015Aldosterone &Aiello EA Villa-Abrille MC Vila Petroff MG, 58 transactivation oftheepidermalgrowthfactorreceptor. Aldosterone stimulatesthecardiacNa(+)/H(+)exchangervia 2011 &Aiello EA Cingolani HE Ennis IL, de Cingolani GE, jc.83.7.2244) Endocrinology andMetabolism patients withapparentmineralocorticoidexcess. 1998 Examinationofgenotypeandphenotyperelationshipsin14 912–919.

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Received in final form 17 October 2016 Accepted 6 November 2016

Journal of Molecular Endocrinology Accepted Preprint published online 7 November 2016