Hypertension affects approximately 1.13 billion adults worldwide and is the leading global risk factor for cardiovascular, cerebrovascular, and kidney diseases. There is emerging evidence that extracellular vesicles participate in the development and progression of hypertension. Extracellular vesicles are membrane-enclosed structures released from nearly all types of eukaryotic cells. During their formation, extracellular vesicles incorporate various parent cell components, including proteins, lipids, and nucleic acids that can be transferred to recipient cells. Extracellular vesicles mediate cell-to-cell communication in a variety of physiological and pathophysiological processes. Therefore, studying the role of circulating and urinary extracellular vesicles in hypertension has the potential to identify novel noninvasive biomarkers and therapeutic targets of different hypertension phenotypes. This review discusses the classification and biogenesis of three EV subcategories (exosomes, microvesicles, and apoptotic bodies) and provides a summary of recent discoveries in the potential impact of extracellular vesicles on hypertension with a specific focus on their role in the blood pressure regulation by organs—artery and kidney, as well as renin-angiotensin-system.
(NCD-RisC) NRFC.Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19·1 million participants. Lancet2017;
389:37–55
2.
MillsKTStefanescuAHeJ.The global epidemiology of hypertension. Nat Rev Nephrol2020;
16:223–37
3.
OlsenMHAngellSYAsmaSBoutouyriePBurgerDChirinosJADamascenoADellesCGimenez-RoqueploAPHeringDLópez-JaramilloPMartinezFPerkovicVRietzschelERSchillaciGSchutteAEScuteriASharmanJEWachtellKWangJG.A call to action and a lifecourse strategy to address the global burden of raised blood pressure on current and future generations: the lancet commission on hypertension. Lancet2016;
388:2665–712
4.
BoweBXieYLiTMokdadAHXianHYanYMaddukuriGAl-AlyZ.Changes in the US burden of chronic kidney disease from 2002 to 2016: an analysis of the global burden of disease study. JAMA Netw Open2018;
1:e184412
5.
ViraniSSAlonsoABenjaminEJBittencourtMSCallawayCWCarsonAPChamberlainAMChangARChengSDellingFNDjousseLElkindMSVFergusonJFFornageMKhanSSKisselaBMKnutsonKLKwanTWLacklandDTLewisTTLichtmanJHLongeneckerCTLoopMSLutseyPLMartinSSMatsushitaKMoranAEMussolinoMEPerakAMRosamondWDRothGASampsonUKASatouGMSchroederEBShahSHShayCMSpartanoNLStokesATirschwellDLVanWagnerLBTsaoCW.Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation2020;
141:e139–e596
6.
ElliottWJ.Improving outcomes in hypertensive patients: focus on adherence and persistence with antihypertensive therapy. J Clin Hypertens2009;
11:376–82
7.
LevyDEhretGBRiceKVerwoertGCLaunerLJDehghanAGlazerNLMorrisonACJohnsonADAspelundTAulchenkoYLumleyTKöttgenAVasanRSRivadeneiraFEiriksdottirGGuoXArkingDEMitchellGFMattace-RasoFUSmithAVTaylorKScharpfRBHwangSJSijbrandsEJBisJHarrisTBGaneshSKO'DonnellCJHofmanARotterJICoreshJBenjaminEJUitterlindenAGHeissGFoxCSWittemanJCBoerwinkleEWangTJGudnasonVLarsonMGChakravartiAPsatyBMvan DuijnCM.Genome-wide association study of blood pressure and hypertension. Nat Genet2009;
41:677–87
8.
ErdbrüggerULeTH.Extracellular vesicles as a novel diagnostic and research tool for patients with HTN and kidney disease. Am J Physiol Renal Physiol2019;
317:F641–7
9.
ErdbrüggerULeTH.Extracellular vesicles in renal diseases: more than novel biomarkers?J Am Soc Nephrol2016;
27:12–26
10.
MerchantMLRoodIMDeegensJKJKleinJB.Isolation and characterization of urinary extracellular vesicles: implications for biomarker discovery. Nat Rev Nephrol2017;
13:731–49
11.
ShahRPatelTFreedmanJE.Circulating extracellular vesicles in human disease. N Engl J Med2018;
379:958–66
WangJMSuCWangYHuangYJYangZChenLWuFXuSYTaoJ.Elevated circulating endothelial microparticles and brachial-ankle pulse wave velocity in well-controlled hypertensive patients. J Hum Hypertens2009;
23:307–15
14.
Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach JM, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Bedina Zavec A, Benmoussa A, Berardi AC, Bergese P, Bielska E, Blenkiron C, Bobis-Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borràs FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan M, Brigstock DR, Brisson A, Broekman ML, Bromberg JF, Bryl-Górecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzás EI, Byrd JB, Camussi G, Carter DR, Caruso S, Chamley LW, Chang YT, Chen C, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro-da-Silva A, Couch Y, Coumans FA, Coyle B, Crescitelli R, Criado MF, D'Souza-Schorey C, Das S, Datta Chaudhuri A, de Candia P, De Santana EF, De Wever O, Del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Dominguez Rubio AP, Dominici M, Dourado MR, Driedonks TA, Duarte FV, Duncan HM, Eichenberger RM, Ekström K, El Andaloussi S, Elie-Caille C, Erdbrügger U, Falcón-Pérez JM, Fatima F, Fish JE, Flores-Bellver M, Försönits A, Frelet-Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gámez-Valero A, Gardiner C, Gärtner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DC, Görgens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH, Hoffmann KF, Holder B, Holthofer H, Hosseinkhani B, Hu G, Huang Y, Huber V, Hunt S, Ibrahim AG, Ikezu T, Inal JM, Isin M, Ivanova A, Jackson HK, Jacobsen S, Jay SM, Jayachandran M, Jenster G, Jiang L, Johnson SM, Jones JC, Jong A, Jovanovic-Talisman T, Jung S, Kalluri R, Kano SI, Kaur S, Kawamura Y, Keller ET, Khamari D, Khomyakova E, Khvorova A, Kierulf P, Kim KP, Kislinger T, Klingeborn M, Klinke DJ, 2nd, Kornek M, Kosanović MM, Kovács Á F, Krämer-Albers EM, Krasemann S, Krause M, Kurochkin IV, Kusuma GD, Kuypers S, Laitinen S, Langevin SM, Languino LR, Lannigan J, Lässer C, Laurent LC, Lavieu G, Lázaro-Ibáñez E, Le Lay S, Lee MS, Lee YXF, Lemos DS, Lenassi M, Leszczynska A, Li IT, Liao K, Libregts SF, Ligeti E, Lim R, Lim SK, Linē A, Linnemannstöns K, Llorente A, Lombard CA, Lorenowicz MJ, Lörincz ÁM, Lötvall J, Lovett J, Lowry MC, Loyer X, Lu Q, Lukomska B, Lunavat TR, Maas SL, Malhi H, Marcilla A, Mariani J, Mariscal J, Martens-Uzunova ES, Martin-Jaular L, Martinez MC, Martins VR, Mathieu M, Mathivanan S, Maugeri M, McGinnis LK, McVey MJ, Meckes DG, Jr., Meehan KL, Mertens I, Minciacchi VR, Möller A, Møller Jørgensen M, Morales-Kastresana A, Morhayim J, Mullier F, Muraca M, Musante L, Mussack V, Muth DC, Myburgh KH, Najrana T, Nawaz M, Nazarenko I, Nejsum P, Neri C, Neri T, Nieuwland R, Nimrichter L, Nolan JP, Nolte-'t Hoen EN, Noren Hooten N, O'Driscoll L, O'Grady T, O'Loghlen A, Ochiya T, Olivier M, Ortiz A, Ortiz LA, Osteikoetxea X, Østergaard O, Ostrowski M, Park J, Pegtel DM, Peinado H, Perut F, Pfaffl MW, Phinney DG, Pieters BC, Pink RC, Pisetsky DS, Pogge von Strandmann E, Polakovicova I, Poon IK, Powell BH, Prada I, Pulliam L, Quesenberry P, Radeghieri A, Raffai RL, Raimondo S, Rak J, Ramirez MI, Raposo G, Rayyan MS, Regev-Rudzki N, Ricklefs FL, Robbins PD, Roberts DD, Rodrigues SC, Rohde E, Rome S, Rouschop KM, Rughetti A, Russell AE, Saá P, Sahoo S, Salas-Huenuleo E, Sánchez C, Saugstad JA, Saul MJ, Schiffelers RM, Schneider R, Schøyen TH, Scott A, Shahaj E, Sharma S, Shatnyeva O, Shekari F, Shelke GV, Shetty AK, Shiba K, Siljander PR, Silva AM, Skowronek A, Snyder OL, 2nd, Soares RP, Sódar BW, Soekmadji C, Sotillo J, Stahl PD, Stoorvogel W, Stott SL, Strasser EF, Swift S, Tahara H, Tewari M, Timms K, Tiwari S, Tixeira R, Tkach M, Toh WS, Tomasini R, Torrecilhas AC, Tosar JP, Toxavidis V, Urbanelli L, Vader P, van Balkom BW, van der Grein SG, Van Deun J, van Herwijnen MJ, Van Keuren-Jensen K, van Niel G, van Royen ME, van Wijnen AJ, Vasconcelos MH, Vechetti IJ, Jr., Veit TD, Vella LJ, Velot É, Verweij FJ, Vestad B, Viñas JL, Visnovitz T, Vukman KV, Wahlgren J, Watson DC, Wauben MH, Weaver A, Webber JP, Weber V, Wehman AM, Weiss DJ, Welsh JA, Wendt S, Wheelock AM, Wiener Z, Witte L, Wolfram J, Xagorari A, Xander P, Xu J, Yan X, Yáñez-Mó M, Yin H, Yuana Y, Zappulli V, Zarubova J, Žėkas V, Zhang JY, Zhao Z, Zheng L, Zheutlin AR, Zickler AM, Zimmermann P, Zivkovic AM, Zocco D, Zuba-Surma EK.
Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.J Extracell Vesicles2018;
7:1535750
15.
MathieuMMartin-JaularLLavieuGThéryC.Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol2019;
21:9–17
16.
KalluriRLeBleuVS.The biology, function, and biomedical applications of exosomes. Science2020;
367:eaau6977
17.
JeppesenDKFenixAMFranklinJLHigginbothamJNZhangQZimmermanLJLieblerDCPingJLiuQEvansRFissellWHPattonJGRomeLHBurnetteDTCoffeyRJ.Reassessment of exosome composition. Cell2019;
177:428–45.e18
18.
StenmarkH.Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol2009;
10:513–25
19.
KastelowitzNYinH.Exosomes and microvesicles: identification and targeting by particle size and lipid chemical probes. Chembiochem2014;
15:923–8
20.
Muralidharan-ChariVClancyJWSedgwickAD'Souza-SchoreyC.Microvesicles: mediators of extracellular communication during cancer progression. J Cell Sci2010;
123:1603–11
21.
FangYWuNGanXYanWMorrellJCGouldSJ.Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol2007;
5:e158
22.
ZhangWZhouXZhangHYaoQLiuYDongZ.Extracellular vesicles in diagnosis and therapy of kidney diseases. Am J Physiol Renal Physiol2016;
311:F844–51
GildeaJJSeatonJEVictorKGReyesCMBigler WangDPettigrewACCourtnerCEShahNTranHTVan SciverRECarlsonJMFelderRA.Exosomal transfer from human renal proximal tubule cells to distal tubule and collecting duct cells. Clin Biochem2014;
47:89–94
26.
TianTZhuYLZhouYYLiangGFWangYYHuFHXiaoZD.Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J Biol Chem2014;
289:22258–67
27.
FengDZhaoWLYeYYBaiXCLiuRQChangLFZhouQSuiSF.Cellular internalization of exosomes occurs through phagocytosis. Traffic2010;
11:675–87
28.
NanboAKawanishiEYoshidaRYoshiyamaH.Exosomes derived from Epstein-Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells. J Virol2013;
87:10334–47
29.
KonoshenkoMYLekchnovEAVlassovAVLaktionovPP.Isolation of extracellular vesicles: general methodologies and latest trends. Biomed Res Int2018;
2018:8545347
30.
Momen-HeraviFBalajLAlianSMantelPYHalleckAETrachtenbergAJSoriaCEOquinSBonebreakCMSaracogluESkogJKuoWP.Current methods for the isolation of extracellular vesicles. Biol Chem2013;
394:1253–62
31.
van der PolEBöingANGoolELNieuwlandR.Recent developments in the nomenclature, presence, isolation, detection and clinical impact of extracellular vesicles. J Thromb Haemost2016;
14:48–56
32.
JacquilletGHoornEJVilasiAUnwinRJ.Urinary vesicles: in splendid isolation. Nephrol Dial Transplant2013;
28:1332–5
33.
ChoiDSKimDKKimYKGhoYS.Proteomics of extracellular vesicles: exosomes and ectosomes. Mass Spectrom Rev2015;
34:474–90
34.
Fernández-LlamaPKhositsethSGonzalesPAStarRAPisitkunTKnepperMA.Tamm-Horsfall protein and urinary exosome isolation. Kidney Int2010;
77:736–42
35.
TaylorDDShahS.Methods of isolating extracellular vesicles impact down-stream analyses of their cargoes. Methods2015;
87:3–10
BurgerDSchockSThompsonCSMontezanoACHakimAMTouyzRM.Microparticles: biomarkers and beyond. Clin Sci2013;
124:423–41
38.
TianYGongMHuYLiuHZhangWZhangMHuXAubertDZhuSWuLYanX.Quality and efficiency assessment of six extracellular vesicle isolation methods by nano-flow cytometry. J Extracell Vesicles2019;
9:1697028
39.
WebberJClaytonA.How pure are your vesicles?J Extracell Vesicles2013;
2:19861
40.
WolfP.The nature and significance of platelet products in human plasma. Br J Haematol1967;
13:269–88
41.
TakahashiAOkadaRNagaoKKawamataYHanyuAYoshimotoSTakasugiMWatanabeSKanemakiMTObuseCHaraE.Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat Commun2017;
8:15287
DavilaMAmirkhosraviACollEDesaiHRoblesLColonJBakerCHFrancisJL.Tissue factor-bearing microparticles derived from tumor cells: impact on coagulation activation. J Thromb Haemost2008;
6:1517–24
44.
MitsuhashiSFeldbrüggeLCsizmadiaEMitsuhashiMRobsonSCMossAC.Luminal extracellular vesicles (EVs) in inflammatory bowel disease (IBD) exhibit proinflammatory effects on epithelial cells and macrophages. Inflamm Bowel Dis2016;
22:1587–95
45.
BarnesTCAndersonMEMootsRJ.The many faces of interleukin-6: the role of IL-6 in inflammation, vasculopathy, and fibrosis in systemic sclerosis. Int J Rheumatol2011;
2011:721608
46.
GulatiKGuhathakurtaSJoshiJRaiNRayA.Cytokines and their role in health and disease: a brief overview. MOJ Immunol2016;
4:1–9
47.
BerckmansRJNieuwlandRKraanMCSchaapMCPotsDSmeetsTJSturkATakPP.Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes. Arthritis Res Ther2005;
7:R536–44
48.
HosseinkhaniBKuypersSvan den AkkerNMSMolinDGMMichielsL.Extracellular vesicles work as a functional inflammatory mediator between vascular endothelial cells and immune cells. Front Immunol2018;
9:1789
49.
ZhaoJSchlößerHAWangZQinJLiJPoppFPoppMCAlakusHChonSHHansenHPNeissWFJauchKWBrunsCJZhaoY.Tumor-derived extracellular vesicles inhibit natural killer cell function in pancreatic cancer. Cancers2019;
11:874
50.
MauseSFvon HundelshausenPZerneckeAKoenenRRWeberC.Platelet microparticles: a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler Thromb Vasc Biol2005;
25:1512–8
51.
GasserOSchifferliJA.Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood2004;
104:2543–8
52.
YangYCZhangNVan CrombruggenKHuGHHongSLBachertC.Transforming growth factor-beta1 in inflammatory airway disease: a key for understanding inflammation and remodeling. Allergy2012;
67:1193–202
LiuZZhangZYaoJXieYDaiQZhangYZhouL.Serum extracellular vesicles promote proliferation of H9C2 cardiomyocytes by increasing miR-17-3p. Biochem Biophys Res Commun2018;
499:441–6
55.
LiuZTanRJLiuY.The many faces of matrix metalloproteinase-7 in kidney diseases. Biomolecules2020;
10:960
56.
BrunoSGrangeCCollinoFDeregibusMCCantaluppiVBianconeLTettaCCamussiG.Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One2012;
7:e33115
57.
EbrahimNAhmedIAHussienNIDessoukyAAFaridASElshazlyAMMostafaOGazzarWBESorourSMSeleemYHusseinAMSabryD.Mesenchymal stem cell-derived exosomes ameliorated diabetic nephropathy by autophagy induction through the mTOR signaling pathway. Cells2018;
7:226
58.
SafaeiRLarsonBJChengTCGibsonMAOtaniSNaerdemannWHowellSB.Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther2005;
4:1595–604
59.
SheddenKXieXTChandaroyPChangYTRosaniaGR.Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. Cancer Res2003;
63:4331–7
60.
SansoneRBaakenMHornPSchulerDWestenfeldRAmabileNKelmMHeissC.Release of endothelial microparticles in patients with arterial hypertension, hypertensive emergencies and catheter-related injury. Atherosclerosis2018;
273:67–74
61.
PrestonRAJyWJimenezJJMauroLMHorstmanLLValleMAimeGAhnYS.Effects of severe hypertension on endothelial and platelet microparticles. Hypertension2003;
41:211–7
62.
HuangPHHuangSSChenYHLinCPChiangKHChenJSTsaiHYLinFYChenJWLinSJ.Increased circulating CD31+/annexin V+ apoptotic microparticles and decreased circulating endothelial progenitor cell levels in hypertensive patients with microalbuminuria. J Hypertens2010;
28:1655–65
63.
GilaniSIWeissgerberTLGarovicVDJayachandranM.Preeclampsia and extracellular vesicles. Curr Hypertens Rep2016;
18:68
64.
SunIOSantelliAAbumoawadAEirinAFergusonCMWoollardJRLermanATextorSCPuranikASLermanLO.Loss of renal peritubular capillaries in hypertensive patients is detectable by urinary endothelial microparticle levels. Hypertension2018;
72:1180–8
65.
OtaniKYokoyaMKodamaTHoriKMatsumotoKOkadaMYamawakiH.Plasma exosomes regulate systemic blood pressure in rats. Biochem Biophys Res Commun2018;
503:776–83
66.
ZhangGLinXShaoYSuCTaoJLiuX.Berberine reduces endothelial injury and arterial stiffness in spontaneously hypertensive rats. Clin Exp Hypertens2020;
42:257–65
67.
GoodMEMusanteLLa SalviaSHowellNLCareyRMLeTHIsaksonBEErdbrüggerU.Circulating extracellular vesicles in normotension restrain vasodilation in resistance arteries. Hypertension2020;
75:218–28
68.
BrownIAMDiederichLGoodMEDeLalioLJMurphySACortese-KrottMMHallJLLeTHIsaksonBE.Vascular smooth muscle remodeling in conductive and resistance arteries in hypertension. Arterioscler Thromb Vasc Biol2018;
38:1969–85
69.
TouyzRMAlves-LopesRRiosFJCamargoLLAnagnostopoulouAArnerAMontezanoAC.Vascular smooth muscle contraction in hypertension. Cardiovasc Res2018;
114:529–39
70.
RosenblumWI.Endothelium-dependent responses in the microcirculation observed in vivo. Acta Physiol2018;
224:e13111
71.
VersariDDaghiniEVirdisAGhiadoniLTaddeiS.Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol2009;
157:527–36
72.
Vásquez-VivarJKalyanaramanBMartásekPHoggNMastersBSKarouiHTordoPPritchardKA.Jr.,
Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A1998;
95:9220–5
73.
SansoneRBaakenMHornPSchulerDWestenfeldRAmabileNKelmMHeissC.Endothelial microparticles and vascular parameters in subjects with and without arterial hypertension and coronary artery disease. Data Brief2018;
19:495–500
74.
FengBChenYLuoYChenMLiXNiY.Circulating level of microparticles and their correlation with arterial elasticity and endothelium-dependent dilation in patients with type 2 diabetes mellitus. Atherosclerosis2010;
208:264–9
75.
LovrenFVermaS.Evolving role of microparticles in the pathophysiology of endothelial dysfunction. Clin Chem2013;
59:1166–74
76.
NomuraSTandonNNNakamuraTConeJFukuharaSKambayashiJ.High-shear-stress-induced activation of platelets and microparticles enhances expression of cell adhesion molecules in THP-1 and endothelial cells. Atherosclerosis2001;
158:277–87
77.
TaguchiKNarimatsuHMatsumotoTKobayashiT.ERK-containing microparticles from a diabetic mouse induce endothelial dysfunction. J Endocrinol2019;
241:221–33
78.
DalliJNorlingLVRenshawDCooperDLeungKYPerrettiM.Annexin 1 mediates the rapid anti-inflammatory effects of neutrophil-derived microparticles. Blood2008;
112:2512–9
79.
ZouXWangJChenCTanXHuangYJosePAYangJZengC.Secreted monocyte miR-27a, via mesenteric arterial mas receptor-eNOS pathway, causes hypertension. Am J Hypertens2020;
33:31–42
80.
RomanMJSabaPSPiniRSpitzerMPickeringTGRosenSAldermanMHDevereuxRB.Parallel cardiac and vascular adaptation in hypertension. Circulation1992;
86:1909–18
81.
AalkjaerCHeagertyAMPetersenKKSwalesJDMulvanyMJ.Evidence for increased media thickness, increased neuronal amine uptake, and depressed excitation–contraction coupling in isolated resistance vessels from essential hypertensives. Circ Res1987;
61:181–6
82.
DucaLBlaiseSRomierBLaffargueMGayralSEl BtaouriHKaweckiCGuillotAMartinyLDebelleLMauriceP.Matrix ageing and vascular impacts: focus on elastin fragmentation. Cardiovasc Res2016;
110:298–308
83.
MulvanyMJ.Small artery remodelling in hypertension. Basic Clin Pharmacol Toxicol2012;
110:49–55
TongYYeCRenXSQiuYZangYHXiongXQWangJJChenQLiYHKangYMZhuGQ.Exosome-Mediated transfer of ACE (Angiotensin-Converting enzyme) from adventitial fibroblasts of spontaneously hypertensive rats promotes vascular smooth muscle cell migration. Hypertension2018;
72:881–8
91.
ZengCVillarVAEisnerGMWilliamsSMFelderRAJosePA.G protein-coupled receptor kinase 4: role in blood pressure regulation. Hypertension2008;
51:1449–55
92.
HallJEGrangerJPdo CarmoJMda SilvaAADubinionJGeorgeEHamzaSSpeedJHallME.Hypertension: physiology and pathophysiology. Compr Physiol2012;
2:2393–442
93.
PisitkunTShenRFKnepperMA.Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A2004;
101:13368–73
94.
ZhouHKajiyamaHTsujiTHuXLeelahavanichkulAVentoSFrankRKoppJBTrachtmanHStarRAYuenPS.Urinary exosomal Wilms' tumor-1 as a potential biomarker for podocyte injury. Am J Physiol Renal Physiol2013;
305:F553–9
95.
KalaniAMohanAGodboleMMBhatiaEGuptaASharmaRKTiwariS.Wilm's tumor-1 protein levels in urinary exosomes from diabetic patients with or without proteinuria. PLoS One2013;
8:e60177
KarpmanDStåhlALArvidssonI.Extracellular vesicles in renal disease. Nat Rev Nephrol2017;
13:545–62
98.
MallegolJvan NielGHeymanM.Phenotypic and functional characterization of intestinal epithelial exosomes. Blood Cells Mol Dis2005;
35:11–6
99.
GonzalesPAPisitkunTHoffertJDTchapyjnikovDStarRAKletaRWangNSKnepperMA.Large-scale proteomics and phosphoproteomics of urinary exosomes. J Am Soc Nephrol2009;
20:363–79
100.
Rojas-VegaLJiménez-VegaARBazúa-ValentiSArroyo-GarzaIJiménezJVGómez-OcádizRCarrillo-PérezDLMorenoEMorales-BuenrostroLEAlberúJGambaG.Increased phosphorylation of the renal Na+-Cl- cotransporter in male kidney transplant recipient patients with hypertension: a prospective cohort. Am J Physiol Renal Physiol2015;
309:F836–42
101.
MayanHAttar-HerzbergDShaharabanyMHoltzmanEJFarfelZ.Increased urinary Na-Cl cotransporter protein in familial hyperkalaemia and hypertension. Nephrol Dial Transplant2008;
23:492–6
102.
TutakhelOAZMoesADValdez-FloresMAKortenoevenMLAVrieMVDJeleńSFentonRAZietseRHoenderopJGJHoornEJHilbrandsLBindelsRJM.NaCl cotransporter abundance in urinary vesicles is increased by calcineurin inhibitors and predicts thiazide sensitivity. PLoS One2017;
12:e0176220
103.
ZacharRJensenBLSvenningsenP.Dietary Na(+) intake in healthy humans changes the urine extracellular vesicle prostasin abundance while the vesicle excretion rate, NCC, and ENaC are not altered. Am J Physiol Renal Physiol2019;
317:F1612–22
104.
Esteva-FontCWangXArsEGuillén-GómezESansLGonzález SaavedraITorresFTorraRMasilamaniSBallarínJA.Fernández-Llama P. Are sodium transporters in urinary exosomes reliable markers of tubular sodium reabsorption in hypertensive patients?Nephron Physiol2010;
114:25–34
105.
HuCCKaterelosMChoySWCrossthwaiteAWalkerSPPellGLeeMCookNMountPFPaizisKPowerDA.Pre-eclampsia is associated with altered expression of the renal sodium transporters NKCC2, NCC and ENaC in urinary extracellular vesicles. PLoS One2018;
13:e0204514
106.
OliveiraRADinizLFTeotônioLOLimaCGMotaRMMartinsASanchesTRSeguroACAndradeLSilvaGBJr.LibórioABDaherEF.Renal tubular dysfunction in patients with American cutaneous leishmaniasis. Kidney Int2011;
80:1099–106
107.
AndersenHFriisUGHansenPBSvenningsenPHenriksenJEJensenBL.Diabetic nephropathy is associated with increased urine excretion of proteases plasmin, prostasin and urokinase and activation of amiloride-sensitive current in collecting duct cells. Nephrol Dial Transplant2015;
30:781–9
108.
QiYWangXRoseKLMacDonaldWHZhangBScheyKLLutherJM.Activation of the endogenous Renin-Angiotensin-Aldosterone system or aldosterone administration increases urinary exosomal sodium channel excretion. J Am Soc Nephrol2016;
27:646–56
109.
GildeaJJCarlsonJMSchoeffelCDCareyRMFelderRA.Urinary exosome miRNome analysis and its applications to salt sensitivity of blood pressure. Clin Biochem2013;
46:1131–4
110.
SalihMFentonRAZietseRHoornEJ.Urinary extracellular vesicles as markers to assess kidney sodium transport. Curr Opin Nephrol Hypertens2016;
25:67–72
111.
GraciaTWangXSuYNorgettEEWilliamsTLMorenoPMicklemG,
Karet Frankl FE. Urinary exosomes contain MicroRNAs capable of paracrine modulation of tubular transporters in kidney. Sci Rep2017;
7:40601
112.
TonneijckLMuskietMHABlijdorpCJSmitsMMTwiskJWKramerMHHDanserAHJDiamantMJolesJAHoornEJvan RaalteDH.Renal tubular effects of prolonged therapy with the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes mellitus. Am J Physiol Renal Physiol2019;
316:F231–f40
113.
AlmeidaLFToftengSSMadsenKJensenBL.Role of the renin-angiotensin system in kidney development and programming of adult blood pressure. Clin Sci2020;
134:641–56
114.
KoboriHNangakuMNavarLGNishiyamaA.The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev2007;
59:251–87
115.
ChappellMC.Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?Am J Physiol Heart Circ Physiol2016;
310:H137–52
116.
Te RietLvan EschJHRoksAJvan den MeirackerAHDanserAH.Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res2015;
116:960–75
117.
PirontiGStrachanRTAbrahamDMon-Wei YuSChenMChenWHanadaKMaoLWatsonLJRockmanHA.Circulating exosomes induced by cardiac pressure overload contain functional angiotensin II type 1 receptors. Circulation2015;
131:2120–30
118.
BurgerDMontezanoACNishigakiNHeYCarterATouyzRM.Endothelial microparticle formation by angiotensin II is mediated via ang II receptor type I/NADPH oxidase/rho kinase pathways targeted to lipid rafts. Arterioscler Thromb Vasc Biol2011;
31:1898–907
119.
MoriyaHKobayashiSOhtakeTTutumiDMochidaYIshiokaKOkaMMaesatoKHidakaSNomuraS.Aliskiren, a direct renin inhibitor, improves vascular endothelial function in patients on hemodialysis independent of antihypertensive effect – a pilot study. Kidney Blood Press Res2013;
37:190–8
120.
de la CuestaFBaldan-MartinMMoreno-LunaRAlvarez-LlamasGGonzalez-CaleroLMourino-AlvarezLSastre-OlivaTLópezJAVázquezJRuiz-HurtadoGSeguraJVivancoFRuilopeLMBarderasMG.Kalirin and CHD7: novel endothelial dysfunction indicators in circulating extracellular vesicles from hypertensive patients with albuminuria. Oncotarget2017;
8:15553–62
121.
Perez-HernandezJOlivaresDFornerMJOrtegaASolazEMartinezFChavesFJRedonJCortesR.Urinary exosome miR-146a is a potential marker of albuminuria in essential hypertension. J Transl Med2018;
16:228
122.
ZhuXBadawiMPomeroySSutariaDSXieZBaekAJiangJElgamalOAMoXPerleKChalmersJSchmittgenTDPhelpsMA.Comprehensive toxicity and immunogenicity studies reveal minimal effects in mice following sustained dosing of extracellular vesicles derived from HEK293T cells. J Extracell Vesicles2017;
6:1324730
123.
LiuBLeeBWNakanishiKVillasanteAWilliamsonRMetzJKimJKanaiMBiLBrownKDi PaoloGHommaSSimsPATopkaraVK.Vunjak-Novakovic G. Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells. Nat Biomed Eng2018;
2:293–303
124.
de AbreuRCFernandesHda Costa MartinsPASahooSEmanueliCFerreiraL.Native and bioengineered extracellular vesicles for cardiovascular therapeutics. Nat Rev Cardiol2020;
17:685–97
125.
MarleauAMChenCSJoyceJATullisRH.Exosome removal as a therapeutic adjuvant in cancer. J Transl Med2012;
10:134
