OpenLB
Open Library of Bioscience
Advanced Search
Histochemistry and cell biology
May, 2022;157 (5): 513-524.

Angiotensin II type 1 receptor localizes at the blood-bile barrier in humans and pigs.

Galyna Pryymachuk, Ehab El-Awaad, Nadin Piekarek, Uta Drebber, Alexandra C Maul, Juergen Hescheler, Andreas Wodarz, Gabriele Pfitzer, Wolfram F Neiss, Markus Pietsch, Mechthild M Schroeter
Author Information
  1. Galyna Pryymachuk: Department of Anatomy I, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany. galyna.pryymachuk@uk-koeln.de. ORCID
  2. Ehab El-Awaad: Institute II of Pharmacology, Center of Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Gleueler Str. 24, 50931, Cologne, Germany. ORCID
  3. Nadin Piekarek: Department of Anatomy I, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany. ORCID
  4. Uta Drebber: Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany. ORCID
  5. Alexandra C Maul: Experimental Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Ostmerheimer Str. 200, 51109, Cologne, Germany. ORCID
  6. Juergen Hescheler: Institute for Neurophysiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Robert-Koch-Str. 39, 50931, Cologne, Germany. ORCID
  7. Andreas Wodarz: Department of Anatomy I, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany. ORCID
  8. Gabriele Pfitzer: Institute of Vegetative Physiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Robert-Koch-Str. 39, 50931, Cologne, Germany. ORCID
  9. Wolfram F Neiss: Department of Anatomy I, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany. ORCID
  10. Markus Pietsch: Institute II of Pharmacology, Center of Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Gleueler Str. 24, 50931, Cologne, Germany. ORCID
  11. Mechthild M Schroeter: Institute for Neurophysiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Robert-Koch-Str. 39, 50931, Cologne, Germany. ORCID
PMID: 35229169 DOI: 10.1007/s00418-022-02087-z

Abstract

Animal models and clinical studies suggest an influence of angiotensin II (AngII) on the pathogenesis of liver diseases via the renin-angiotensin system. AngII application increases portal blood pressure, reduces bile flow, and increases permeability of liver tight junctions. Establishing the subcellular localization of angiotensin II receptor type 1 (AT1R), the main AngII receptor, helps to understand the effects of AngII on the liver. We localized AT1R in situ in human and porcine liver and porcine gallbladder by immunohistochemistry. In order to do so, we characterized commercial anti-AT1R antibodies regarding their capability to recognize heterologous human AT1R in immunocytochemistry and on western blots, and to detect AT1R using overlap studies and AT1R-specific blocking peptides. In hepatocytes and canals of Hering, AT1R displayed a tram-track-like distribution, while in cholangiocytes AT1R appeared in a honeycomb-like pattern; i.e., in liver epithelia, AT1R showed an equivalent distribution to that in the apical junctional network, which seals bile canaliculi and bile ducts along the blood-bile barrier. In intrahepatic blood vessels, AT1R was most prominent in the tunica media. We confirmed AT1R localization in situ to the plasma membrane domain, particularly between tight and adherens junctions in both human and porcine hepatocytes, cholangiocytes, and gallbladder epithelial cells using different anti-AT1R antibodies. Localization of AT1R at the junctional complex could explain previously reported AngII effects and predestines AT1R as a transmitter of tight junction permeability.

Keywords

AT1R Canals of Hering Gallbladder Human liver Porcine liver Tight junctions

References

Afroze SH, Munshi MK, Martinez AK, Uddin M, Gergely M, Szynkarski C, Guerrier M, Nizamutdinov D, Dostal D, Glaser S (2015) Activation of the renin–angiotensin system stimulates biliary hyperplasia during cholestasis induced by extrahepatic bile duct ligation. Am J Physiol Gastrointest Liver Physiol 308:G691-701 [PMID: 25678505]
Anderson JM, Glade JL, Stevenson BR, Boyer JL, Mooseker MS (1989) Hepatic immunohistochemical localization of the tight junction protein ZO-1 in rat models of cholestasis. Am J Pathol 134:1055–1062 [PMID: 2719075]
Bataller R, Gines P, Nicolas JM, Gorbig MN, Garcia-Ramallo E, Gasull X, Bosch J, Arroyo V, Rodes J (2000) Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 118:1149–1156 [PMID: 10833490]
Bataller R, Sancho-Bru P, Gines P, Lora JM, Al-Garawi A, Sole M, Colmenero J, Nicolas JM, Jimenez W, Weich N, Gutierrez-Ramos JC, Arroyo V, Rodes J (2003) Activated human hepatic stellate cells express the renin–angiotensin system and synthesize angiotensin II. Gastroenterology 125:117–125 [PMID: 12851877]
Bianciotti LG, Vatta MS, Dominguez AE, Vescina C, Castro JL, Magarinos J, Fernandez BE (1994) Quantitative modifications induced by angiotensin II on rat bile secretion. Regul Pept 54:429–437 [PMID: 7716276]
Booz GW, Conrad KM, Hess AL, Singer HA, Baker KM (1992) Angiotensin-II-binding sites on hepatocyte nuclei. Endocrinology 130:3641–3649 [PMID: 1597161]
Burton L, Scaife P, Paine SW, Mellor HR, Abernethy L, Littlewood P, Rauch C (2020) Hydrostatic pressure regulates CYP1A2 expression in human hepatocytes via a mechanosensitive aryl hydrocarbon receptor-dependent pathway. Am J Physiol Cell Physiol 318:C889–C902 [PMID: 32159360]
Campanile CP, Crane JK, Peach MJ, Garrison JC (1982) The hepatic angiotensin II receptor. I. Characterization of the membrane-binding site and correlation with physiological response in hepatocytes. J Biol Chem 257:4951–4958 [PMID: 6279653]
Cuerrier CM, Benoit M, Guillemette G, Gobeil F Jr, Grandbois M (2009) Real-time monitoring of angiotensin II-induced contractile response and cytoskeleton remodeling in individual cells by atomic force microscopy. Pflugers Arch 457:1361–1372 [PMID: 18953565]
Dasgupta C, Zhang L (2011) Angiotensin II receptors and drug discovery in cardiovascular disease. Drug Discov Today 16:22–34 [PMID: 21147255]
de Almeida JB, Holtzman EJ, Peters P, Ercolani L, Ausiello DA, Stow JL (1994) Targeting of chimeric G alpha i proteins to specific membrane domains. J Cell Sci 107(Pt 3):507–515 [PMID: 8006069]
De Mello WC (2012) Mechanical stretch reduces the effect of angiotensin II on potassium current in cardiac ventricular cells of adult Sprague Dawley rats. On the role of AT1 receptors as mechanosensors. J Am Soc Hypertens 6:369–374 [PMID: 23063532]
Dodane V, Kachar B (1996) Identification of isoforms of G proteins and PKC that colocalize with tight junctions. J Membr Biol 149:199–209 [PMID: 8801352]
Durvasula RV, Petermann AT, Hiromura K, Blonski M, Pippin J, Mundel P, Pichler R, Griffin S, Couser WG, Shankland SJ (2004) Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 65:30–39 [PMID: 14675034]
Fonseca MI, Brown RD (1997) Immunocytochemical methods for investigating receptor localization. Methods Mol Biol 83:91–106 [PMID: 9210139]
Gasc JM, Shanmugam S, Sibony M, Corvol P (1994) Tissue-specific expression of type 1 angiotensin II receptor subtypes. An in situ hybridization study. Hypertension 24:531–537 [PMID: 7960011]
Grosse B, Cassio D, Yousef N, Bernardo C, Jacquemin E, Gonzales E (2012) Claudin-1 involved in neonatal ichthyosis sclerosing cholangitis syndrome regulates hepatic paracellular permeability. Hepatology 55:1249–1259 [PMID: 22030598]
Gunther S, Alexander RW, Atkinson WJ, Gimbrone MA Jr (1982) Functional angiotensin II receptors in cultured vascular smooth muscle cells. J Cell Biol 92:289–298 [PMID: 6277961]
Hung MC, Link W (2011) Protein localization in disease and therapy. J Cell Sci 124:3381–3392 [PMID: 22010196]
Itzhak DN, Tyanova S, Cox J, Borner GH (2016) Global, quantitative and dynamic mapping of protein subcellular localization. Elife 5:e16950 [PMID: 27278775]
Keon BH, Schafer S, Kuhn C, Grund C, Franke WW (1996) Symplekin, a novel type of tight junction plaque protein. J Cell Biol 134:1003–1018 [PMID: 8769423]
Khayat RN, Varadharaj S, Porter K, Sow A, Jarjoura D, Gavrilin MA, Zweier JL (2018) Angiotensin receptor expression and vascular endothelial dysfunction in obstructive sleep apnea. Am J Hypertens 31:355–361 [PMID: 29036393]
Kim TH, Yang YM, Han CY, Koo JH, Oh H, Kim SS, You BH, Choi YH, Park TS, Lee CH, Kurose H, Noureddin M, Seki E, Wan YY, Choi CS, Kim SG (2018) Galpha12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration. J Clin Investig 128:5587–5602 [PMID: 30300140]
Kojima T, Yamamoto T, Murata M, Chiba H, Kokai Y, Sawada N (2003) Regulation of the blood-biliary barrier: interaction between gap and tight junctions in hepatocytes. Med Electron Microsc 36:157–164 [PMID: 14505059]
Leung PS, Suen PM, Ip SP, Yip CK, Chen G, Lai PB (2003) Expression and localization of AT1 receptors in hepatic Kupffer cells: its potential role in regulating a fibrogenic response. Regul Pept 116:61–69 [PMID: 14599716]
Li Y, Xiong F, Xu W, Liu S (2019) Increased serum angiotensin II is a risk factor of nonalcoholic fatty liver disease: a prospective pilot study. Gastroenterol Res Pract 2019:5647161 [PMID: 31827504]
Lowe PJ, Miyai K, Steinbach JH, Hardison WG (1988) Hormonal regulation of hepatocyte tight junctional permeability. Am J Physiol 255:G454-461 [PMID: 2845804]
Mederosy Schnitzler M, Storch U, Gudermann T (2011) AT1 receptors as mechanosensors. Curr Opin Pharmacol 11:112–116 [DOI: 10.1016/j.coph.2010.11.003]
Mensa L, Crespo G, Gastinger MJ, Kabat J, Perez-del-Pulgar S, Miquel R, Emerson SU, Purcell RH, Forns X (2011) Hepatitis C virus receptors claudin-1 and occludin after liver transplantation and influence on early viral kinetics. Hepatology 53:1436–1445 [PMID: 21294144]
Meyer TN, Schwesinger C, Denker BM (2002) Zonula occludens-1 is a scaffolding protein for signaling molecules. Galpha(12) directly binds to the Src homology 3 domain and regulates paracellular permeability in epithelial cells. J Biol Chem 277:24855–24858 [PMID: 12023272]
Munshi MK, Wise C, Yang FQ, Dostal DE, Glaser SS (2010) Mechanical stretch stimulates cholangiocyte proliferation and profibrotic gene expression. FASEB J 24(1000):5
Munshi MK, Uddin MN, Glaser SS (2011) The role of the renin–angiotensin system in liver fibrosis. Exp Biol Med (Maywood) 236:557–566 [DOI: 10.1258/ebm.2011.010375]
Nemeth Z, Szasz AM, Somoracz A, Tatrai P, Nemeth J, Gyorffy H, Szijarto A, Kupcsulik P, Kiss A, Schaff Z (2009) Zonula occludens-1, occludin, and E-cadherin protein expression in biliary tract cancers. Pathol Oncol Res 15:533–539 [PMID: 19184677]
Novikoff PM, Cammer M, Tao L, Oda H, Stockert RJ, Wolkoff AW, Satir P (1996) Three-dimensional organization of rat hepatocyte cytoskeleton: relation to the asialoglycoprotein endocytosis pathway. J Cell Sci 109(Pt 1):21–32 [PMID: 8834787]
Paizis G, Cooper ME, Schembri JM, Tikellis C, Burrell LM, Angus PW (2002) Up-regulation of components of the renin–angiotensin system in the bile duct-ligated rat liver. Gastroenterology 123:1667–1676 [PMID: 12404241]
Patel T (2003) Aberrant local renin–angiotensin II responses in the pathogenesis of primary sclerosing cholangitis. Med Hypotheses 61:64–67 [PMID: 12781643]
Paxton WG, Runge M, Horaist C, Cohen C, Alexander RW, Bernstein KE (1993) Immunohistochemical localization of rat angiotensin II AT1 receptor. Am J Physiol 264:F989-995 [PMID: 7686719]
Pryymachuk G, Polykandriotis E, Schievenbusch S, Arkudas A, Nierhoff D, Curth HM, Odenthal M, Horch RE, Neiss WF, Goeser T, Steffen HM, Toex U (2013) Vital staining of blood vessels and bile ducts with carboxyfluorescein diacetate succinimidyl ester: a novel tool for isolation of cholangiocytes. Histol Histopathol 28:1013–1020 [PMID: 23456592]
Ramkhelawon B, Rivas D, Lehoux S (2013) Shear stress activates extracellular signal-regulated kinase 1/2 via the angiotensin II type 1 receptor. FASEB J 27:3008–3016 [PMID: 23585396]
Saxena R, Theise N (2004) Canals of Hering: recent insights and current knowledge. Semin Liver Dis 24:43–48 [PMID: 15085485]
Scholtholt J, Shiraishi T (1968) Action of acetylcholine, bradykinin and angiotensin on the liver blood flow of the anesthetized dog and on the pressure in the ligated ductus choledochus. Pflugers Arch Gesamte Physiol Menschen Tiere 300:189–201 [PMID: 4298880]
Schroeder DC, Guschlbauer M, Maul AC, Cremer DA, Becker I, de la Puente BD, Paal P, Padosch SA, Wetsch WA, Annecke T, Bottiger BW, Sterner-Kock A, Herff H (2017) Oesophageal heat exchangers with a diameter of 11 mm or 14.7 mm are equally effective and safe for targeted temperature management. PLoS One 12:e0173229 [PMID: 28291783]
Schulte S, Oidtmann A, Kociok N, Demir M, Odenthal M, Drebber U, Dienes HP, Nierhoff D, Goeser T, Toex U, Steffen HM (2009) Hepatocyte expression of angiotensin II type 1 receptor is downregulated in advanced human liver fibrosis. Liver Int 29:384–391 [PMID: 19040540]
Sen I, Jim KF, Soffer RL (1983) Solubilization and characterization of an angiotensin II binding protein from liver. Eur J Biochem 136:41–49 [PMID: 6311548]
Shatanawi A, Romero MJ, Iddings JA, Chandra S, Umapathy NS, Verin AD, Caldwell RB, Caldwell RW (2011) Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway. Am J Physiol Cell Physiol 300:C1181-1192 [PMID: 21289285]
Shim KY, Eom YW, Kim MY, Kang SH, Baik SK (2018) Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension. Korean J Intern Med 33:453–461 [PMID: 29462546]
Shirai H, Takahashi K, Katada T, Inagami T (1995) Mapping of G protein coupling sites of the angiotensin II type 1 receptor. Hypertension 25:726–730 [PMID: 7721423]
Simoes ESAC, Miranda AS, Rocha NP, Teixeira AL (2017) Renin angiotensin system in liver diseases: friend or foe? World J Gastroenterol 23:3396–3406 [DOI: 10.3748/wjg.v23.i19.3396]
St-Pierre D, Cabana J, Holleran BJ, Besserer-Offroy E, Escher E, Guillemette G, Lavigne P, Leduc R (2018) Angiotensin II cyclic analogs as tools to investigate AT1R biased signaling mechanisms. Biochem Pharmacol 154:104–117 [PMID: 29684376]
Sturzeneker MCS, de Noronha L, Olandoski M, Wendling LU, Precoma DB (2019) Ramipril significantly attenuates the development of non-alcoholic steatohepatitis in hyperlipidaemic rabbits. Am J Cardiovasc Dis 9:8–17 [PMID: 31131153]
Tanimizu N, Ichinohe N, Sasaki Y, Itoh T, Sudo R, Yamaguchi T, Katsuda T, Ninomiya T, Tokino T, Ochiya T, Miyajima A, Mitaka T (2021) Generation of functional liver organoids on combining hepatocytes and cholangiocytes with hepatobiliary connections ex vivo. Nat Commun 12:3390 [PMID: 34099675]
Touyz RM, Schiffrin EL (2000) Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev 52:639–672 [PMID: 11121512]
Tsukada N, Phillips MJ (1993) Bile canalicular contraction is coincident with reorganization of pericanalicular filaments and co-localization of actin and myosin-II. J Histochem Cytochem 41:353–363 [PMID: 7679126]
van Eyken P, Sciot R, van Damme B, de Wolf-Peeters C, Desmet VJ (1987) Keratin immunohistochemistry in normal human liver. Cytokeratin pattern of hepatocytes, bile ducts and acinar gradient. Virchows Arch A Pathol Anat Histopathol 412:63–72 [PMID: 2446418]
Wang YJ, Gregory RB, Barritt GJ (2000) Regulation of F-actin and endoplasmic reticulum organization by the trimeric G-protein Gi2 in rat hepatocytes. Implication for the activation of store-operated Ca2+ inflow. J Biol Chem 275:22229–22237 [PMID: 10787407]
Wang C, Qian X, Sun X, Chang Q (2015) Angiotensin II increases matrix metalloproteinase 2 expression in human aortic smooth muscle cells via AT1R and ERK1/2. Exp Biol Med (Maywood) 240:1564–1571 [DOI: 10.1177/1535370215576312]
Yuan X, Li J, Coulouarn C, Lin T, Sulpice L, Bergeat D, De La Torre C, Liebe R, Gretz N, Ebert MPA, Dooley S, Weng HL (2018) SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance. Br J Cancer 119:1358–1366 [PMID: 30420613]
Zhang X, Wang H, Duvernay MT, Zhu S, Wu G (2013) The angiotensin II type 1 receptor C-terminal Lys residues interact with tubulin and modulate receptor export trafficking. PLoS One 8:e57805 [PMID: 23451270]
Zhou L, Pradhan-Sundd T, Poddar M, Singh S, Kikuchi A, Stolz DB, Shou W, Li Z, Nejak-Bowen KN, Monga SP (2015) Mice with hepatic loss of the desmosomal protein gamma-catenin are prone to cholestatic injury and chemical carcinogenesis. Am J Pathol 185:3274–3289 [PMID: 26485505]
Zong H, Yin B, Zhou H, Cai D, Ma B, Xiang Y (2015) Loss of angiotensin-converting enzyme 2 promotes growth of gallbladder cancer. Tumour Biol 36:5171–5177 [PMID: 25663464]

Grants

  1. INST 1856/66-1 FUGG/Deutsche Forschungsgemeinschaft
  2. A/12/93239/German Academic Exchange Service-German Egyptian Research Long-Term scholarship
  3. 91541390/German Academic Exchange Service-German Egyptian Research Long-Term scholarship
  4. N14/Graduate Program in Pharmacology and Experimental Therapeutics of the University of Cologne and Bayer Healthcare

MeSH Term

Angiotensin II
Animals
Bile
Blotting, Western
Humans
Peptides
Receptor, Angiotensin, Type 1
Receptor, Angiotensin, Type 2
Swine

Chemicals

Peptides
Receptor, Angiotensin, Type 1
Receptor, Angiotensin, Type 2
Angiotensin II
Journal Article

Word Cloud

Similar Articles

Cited By