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Renin-Angiotensin System/Blood Pressure Control

  • Chapter
Transgenic Models in Pharmacology

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 159))

  • 124 Accesses

Abstract

The control of blood pressure is achieved by a complex interplay of several hormonal systems acting either in an endocrine manner or locally in tissues such as brain, vessels, and kidney in a paracrine or autocrine manner. Because of the complexity of the cardiovascular system and its regulation, the study of these processes has been by and large limited to the whole organismic level. Thus, transgenic technology has been of the highest importance in recent years to assist in the discovery of the role of specific gene products in cardiovascular regulation. This review summarizes such findings about peptide systems involved in blood pressure control with a major emphasis on the renin-angiotensin system, which cardiovascularly may be the most relevant system. Also, transgenic animals with targeted genetic alterations in the synthesis or action of kinins, endothelins, natriuretic peptides, as well as adrenomedullin and the calcitonin gene-related peptide (CGRP) are described. For the renin-angiotensin system, all components have been deleted by gene targeting. Whenever angiotensin II synthesis or action was completely blunted, such as by the deletion of renin, angiotensinogen, angiotensin-converting enzyme, or the angiotensin II AT1 receptor, the mice showed very low blood pressure, kidney dysmorphology, and a high mortality. In contrast, most transgenic rat or mouse models overexpressing renin or angiotensinogen became hypertensive. Transgenic rats with reduced angiotensinogen in the brain are hypotensive and accordingly mice with enhanced angiotensin II generation in the central nervous system exhibited increased blood pressure, supporting an important role of the central renin-angiotensin system in cardiovascular control. Mice lacking endothelins or its receptors revealed functions of these peptides going beyond blood pressure regulation and implicating the endothelin system in the development of neural crestderived cells. Novel transgenic technologies such as inducible conditional gene targeting will help to further this knowledge and to design new therapeutic strategies.

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References

  • Alfie ME, Yang XP, Hess F, Carretero OA (1996) Salt-sensitive hypertension in bradykinin B2 receptor knockout mice. Biochem Biophys Res Commun 224:625–630

    PubMed  CAS  Google Scholar 

  • Araujo RC, Kettritz R, Fichtner I, Paiva AC, Pesquero JB, Bader M (2001) Altered neutrophil homeostasis in kinin B1 receptor-deficient mice. Biol Chem 382:91–95

    PubMed  CAS  Google Scholar 

  • Bader M, Bohnemeier H, Zollmann FS, Lockley-Jones OE, Ganten D (2000) Transgenic animals in cardiovascular disease research. Exp Physiol 85:713–731

    PubMed  CAS  Google Scholar 

  • Baltatu O, Afeche SC, Jose dos Santos SH, Campos LA, Barbosa R, Michelini LC, Bader M, Cipolla-Neto J (2002) Locally synthesized angiotensin modulates pineal melatonin generation. J Neurochem 80:328–334

    PubMed  CAS  Google Scholar 

  • Baltatu O, Janssen BJ, Bricca G, Plehm R, Monti J, Ganten D, Bader M (2001) Alterations in blood pressure and heart rate variability in transgenic rats with low brain angiotensinogen. Hypertension 37:408–413

    PubMed  CAS  Google Scholar 

  • Baynash AG, Hosoda K, Giaid A, Richardson JA, Emoto N, Hammer RE, Yanagisawa M (1994) Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79:1277–1285

    PubMed  CAS  Google Scholar 

  • Bergaya S, Meneton P, Bloch-Faure M, Mathieu E, Alhenc-Gelas F, Levy BI, Boulanger CM (2001) Decreased flow-dependent dilation in carotid arteries of tissue kallikreinknockout mice. Circ Res 88:593–599

    PubMed  CAS  Google Scholar 

  • Bertaux F, Colledge WH, Smith SE, Evans M, Samani NJ, Miller CC (1997) Normotensive blood pressure in mice with a disrupted renin Ren-1d gene. Transgenic Res 6:191–196

    PubMed  CAS  Google Scholar 

  • Bohlen und Halbach O., Walther T, Bader M, Albrecht D (2001) Genetic deletion of angiotensin AT2 receptor leads to increased cell numbers in different brain structures of mice. Regul Pept 99:209–216

    Google Scholar 

  • Bohlender J, Fukamizu A, Lippoldt A, Nomura T, Dietz R, Menard J, Murakami K, Luft FC, Ganten D (1997) High human renin hypertension in transgenic rats. Hypertension 29:428–434

    PubMed  CAS  Google Scholar 

  • Bohlender J, Ganten D, Luft FC (2000) Rats transgenic for human renin and human angiotensinogen as a model for gestational hypertension. J Am Soc Nephrol 11:2056–2061

    PubMed  CAS  Google Scholar 

  • Borgonio A, Pummer S, Witte K, Lemmer B (2001) Reduced baroreflex sensitivity and blunted endogenous nitric oxide synthesis precede the development of hypertension in TGR(mREN2)27 rats. Chronobiol Int 18:215–226

    PubMed  CAS  Google Scholar 

  • Borkowski JA, Ransom RW, Seabrook GR, Trumbauer M, Chen H, Hill RG, Strader CD, Hess JF (1995) Targeted disruption of a B2 bradykinin receptor gene in mice eliminates bradykinin action in smooth muscle and neurons. J Biol Chem 270:13706–13710

    PubMed  CAS  Google Scholar 

  • Brenin DR, Bader M, Hübner N, Levan G, Iannaccone PM (1997) Rat embryonic stem cells: A progress report. Transplantation Proc 29:1761–1765

    CAS  Google Scholar 

  • Campbell DJ, Rong P, Kladis A, Rees B, Ganten D, Skinner SL (1995) Angiotensin and bradykinin peptides in the TGR(mRen-2)27 rat. Hypertension 25:1014–1020

    PubMed  CAS  Google Scholar 

  • Carlson SH, Oparil S, Chen YF, Wyss JM (2002) Blood pressure and NaCl-sensitive hypertension are influenced by angiotensin-converting enzyme gene expression in transgenic mice. Hypertension 39:214–218

    PubMed  CAS  Google Scholar 

  • Carpenter C, Honkanen AA, Mashimo H, Goss KA, Huang P, Fishman MC, Asaad M, Dorso CR, Cheung H (1996) Renal abnormalities in mutant mice. Nature 380:292–292

    PubMed  CAS  Google Scholar 

  • Cervenka L, Harrison-Bernard LM, Dipp S, Primrose G, Imig JD, El-Dahr SS (1999) Early onset salt-sensitive hypertension in bradykinin B2 receptor null mice. Hypertension 34:176–180

    PubMed  CAS  Google Scholar 

  • Chen X, Li W, Yoshida H, Tsuchida S, Nishimura H, Takemoto F, Okubo S, Fogo A, Matsusaka T, Ichikawa I (1997) Targeting deletion of angiotensin type 1B receptor gene in the mouse. Am J Physiol 272: F299–F304

    PubMed  CAS  Google Scholar 

  • Chesne P, Adenot PG, Viglietta C, Baratte M, Boulanger L, Renard JP (2002) Cloned rabbits produced by nuclear transfer from adult somatic cells. Nat Biotechnol 20:366–369

    PubMed  CAS  Google Scholar 

  • Chusho H, Tamura N, Ogawa Y, Yasoda A, Suda M, Miyazawa T, Nakamura K, Nakao K, Kurihara T, Komatsu Y, Itoh H, Tanaka K, Saito Y, Katsuki M, Nakao K (2001) Dwarfism and early death in mice lacking C-type natriuretic peptide. Proc Natl Acad Sci U S A 98:4016–4021

    PubMed  CAS  Google Scholar 

  • Clark AF, Sharp MGF, Morley SD, Fleming S, Peters J, Mullins JJ (1997) Renin-1 is essential for normal renal juxtaglomerular cell granulation and macula densa morphology. J Biol Chem 272:18185–18190

    PubMed  CAS  Google Scholar 

  • Clouthier DE, Hosoda K, Richardson JA, Williams SC, Yanagisawa H, Kuwaki T, Kumada M, Hammer RE, Yanagisawa M (1998) Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125:813–824

    PubMed  CAS  Google Scholar 

  • Cole J, Quach dL, Sundaram K, Corvol P, Capecchi MR, Bernstein KE (2002) Mice lacking endothelial angiotensin-converting enzyme have a normal blood pressure. Circ Res 90:87–92

    PubMed  CAS  Google Scholar 

  • Davisson RL, Ding Y, Stec DE, Catterall JF, Sigmund CD (1999) Novel mechanism of hypertension revealed by cell-specific targeting of human angiotensinogen in transgenic mice. Physiol Genomics 1:3–9

    PubMed  CAS  Google Scholar 

  • Davisson RL, Oliverio MI, Coffman TM, Sigmund CD (2000) Divergent functions of angiotensin II receptor isoforms in the brain. J Clin Invest 106:103–106

    PubMed  CAS  Google Scholar 

  • Davisson RL, Yang G, Beltz TG, Cassell MD, Johnson AK, Sigmund CD (1998) The brain renin-angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes. Circ Res 83:1047–1058

    PubMed  CAS  Google Scholar 

  • Ding Y, Stec DE, Sigmund CD (2001) Genetic evidence that lethality in angiotensinogendeficient mice is due to loss of systemic but not renal angiotensinogen. J Biol Chem 276:7431–7436

    PubMed  CAS  Google Scholar 

  • Diz DI, Westwood B, Bosch SM, Ganten D, Ferrario C (1998) NK1 receptor antagonist blocks angiotensin II responses in renin transgenic rat medulla oblongata. Hypertension 31:473–479

    PubMed  CAS  Google Scholar 

  • Doan TN, Gletsu N, Cole J, Bernstein KE (2001) Genetic manipulation of the renin-angiotensin system. Curr Opin Nephrol Hypertens 10:483–491

    PubMed  CAS  Google Scholar 

  • Emanueli C, Bonaria SM, Stacca T, Pintus G, Kirchmair R, Isner JM, Pinna A, Gaspa L, Regoli D, Cayla C, Pesquero JB, Bader M, Madeddu P (2002) Targeting kinin B(1) receptor for therapeutic neovascularization. Circulation 105:360–366

    PubMed  CAS  Google Scholar 

  • Emanueli C, Maestri R, Corradi D, Marchioni R, Minasi A, Tozzi MG, Salis MB, Straino S, Capogrossi MC, Olivetti G, Madeddu P (1999) Dilated and failing cardiomyopathy in bradykinin B(2) receptor knockout mice. Circulation 100:2359–2365

    PubMed  CAS  Google Scholar 

  • Esther CR, Marino EM, Howard TE, Machaud A, Corvol P, Capecchi MR, Bernstein KE (1997) The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice. J Clin Invest 99:2375–2385

    PubMed  CAS  Google Scholar 

  • Esther CR, Jr., Howard TE, Marino EM, Goddard JM, Capecchi MR, Bernstein KE (1996) Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest 74:953–965

    PubMed  CAS  Google Scholar 

  • Ferreira J, Campos MM, Pesquero JB, Araujo RC, Bader M, Calixto JB (2001) Evidence for the participation of kinins in Freund’s adjuvant-induced inflammatory and nociceptive responses in kinin B(1) and B(2) receptor knockout mice. Neuropharmacology 41:1006–1012

    PubMed  CAS  Google Scholar 

  • Fukamizu A, Seo MS, Hatae T, Yokoyama M, Nomura T, Katsuki M, Murakami K (1989) Tissue-specific expression of the human renin gene in transgenic mice. Biochem Biophys Res Commun 165:826–832

    PubMed  CAS  Google Scholar 

  • Fukamizu A, Sugimura K, Takimoto E, Sugiyama F, Seo MS, Takahashi S, Hatae T, Kajiwara N, Yagami K, Murakami K (1993) Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes. J Biol Chem 268:11617–11621

    PubMed  CAS  Google Scholar 

  • Gangula PR, Zhao H, Supowit SC, Wimalawansa SJ, Dipette DJ, Westlund KN, Gagel RF, Yallampalli C (2000) Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene knockout mice. Hypertension 35:470–475

    PubMed  CAS  Google Scholar 

  • Ganten D, Wagner J, Zeh K, Bader M, Michel J-B, Paul M, Zimmermann F, Ruf P, Hilgenfeldt U, Ganten U, Kaling M, Bachmann S, Fukamizu A, Mullins JJ, Murakami K (1992) Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes. Proc Natl Acad Sci USA 89:7806–7810

    PubMed  CAS  Google Scholar 

  • Gariepy CE, Ohuchi T, Williams SC, Richardson JA, Yanagisawa M (2000) Salt-sensitive hypertension in endothelin-B receptor-deficient rats. J Clin Invest 105:925–933

    PubMed  CAS  Google Scholar 

  • Gariepy CE, Williams SC, Richardson JA, Hammer RE, Yanagisawa M (1998) Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease. J Clin Invest 102:1092–1101

    PubMed  CAS  Google Scholar 

  • Gross V, Milia AF, Plehm R, Inagami T, Luft FC (2000a) Lonγ-term blood pressure telemetry in AT2 receptor-disrupted mice. J Hypertens 18:955–961

    PubMed  CAS  Google Scholar 

  • Gross V, Schunck WH, Honeck H, Milia AF, Kargel E, Walther T, Bader M, Inagami T, Schneider W, Luft FC (2000b) Inhibition of pressure natriuresis in mice lacking the AT2 receptor. Kidney Int 57:191–202

    PubMed  CAS  Google Scholar 

  • Gross V, Walther T, Milia AF, Walter K, Schneider W, Luft FC (2001) Left ventricular function in mice lacking the AT2 receptor. J Hypertens 19:967–976

    PubMed  CAS  Google Scholar 

  • Hein L, Barsh GS, Pratt RE, Dzau VJ, Kobilka BK (1995) Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Nature 377:744–747

    PubMed  CAS  Google Scholar 

  • Hein L, Stevens ME, Barsh GS, Pratt RE, Kobilka BK, Dzau VJ (1997) Overexpression of angiotensin AT1 receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block. Proc Natl Acad Sci USA 94:6391–6396

    PubMed  CAS  Google Scholar 

  • Hocher B, Liefeldt L, Thone-Reineke C, Orzechowski HD, Distler A, Bauer C, Paul M (1996) Characterization of the renal phenotype of transgenic rats expressing the human endothelin-2 gene. Hypertension 28:196–201

    PubMed  CAS  Google Scholar 

  • Hocher B, Thone-Reineke C, Rohmeiss P, Schmager F, Slowinski T, Burst V, Siegmund F, Quertermous T, Bauer C, Neumayer HH, Schleuning WD, Theuring F (1997) Endo-thelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest 99:1380–1389

    PubMed  CAS  Google Scholar 

  • Hoffmann S, Krause T, van Geel PP, Willenbrock R, Pagel I, Pinto YM, Buikema H, Van Gilst WH, Lindschau C, Paul M, Inagami T, Ganten D, Urata H (2001) Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy. J Mol Med 79:601–608

    PubMed  CAS  Google Scholar 

  • Holtwick R, Gotthardt M, Skryabin B, Steinmetz M, Potthast R, Zetsche B, Hammer RE, Herz J, Kuhn M (2002) Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc Natl Acad Sci USA 99:7142–7147

    PubMed  CAS  Google Scholar 

  • Hosoda K, Hammer RE, Richardson JA, Baynash AG, Cheung JC, Giaid A, Yanagisawa M (1994) Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79:1267–1276

    PubMed  CAS  Google Scholar 

  • Huang W, Gallois Y, Bouby N, Bruneval P, Heudes D, Belair MF, Krege JH, Meneton P, Marre M, Smithies O, Alhenc-Gelas F (2001) Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse. Proc Natl Acad Sci USA 98:13330–13334

    PubMed  CAS  Google Scholar 

  • Ichihara S, Senbonmatsu T, Price E, Jr., Ichiki T, Gaffney FA, Inagami T (2001) Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation 104:346–351

    PubMed  CAS  Google Scholar 

  • Ichiki T, Labosky PA, Shiota C, Okuyama S, Imagawa Y, Fogo A, Niimura F, Ichikawa I, Hogan BL, Inagami T (1995) Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature 377:748–750

    PubMed  CAS  Google Scholar 

  • Ito M, Oliverio MI, Mannon PJ, Best CF, Maeda N, Smithies O, Coffman TM (1995) Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci USA 92:3521–3525

    PubMed  CAS  Google Scholar 

  • Jackson TR, Blair AC, Marshall J, Goedert M, Hanley MR (1988) The mas oncogene encodes an angiotensin receptor. Nature 335:437–440

    PubMed  CAS  Google Scholar 

  • John SW, Krege JH, Oliver PM, Hagaman JR, Hodgin JB, Pang SC, Flynn TG, Smithies O (1995) Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 267:679–681

    PubMed  CAS  Google Scholar 

  • Ju H, Gros R, You X, Tsang S, Husain M, Rabinovitch M (2001) Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice. Proc Natl Acad Sci U S A 98:7469–7474

    PubMed  CAS  Google Scholar 

  • Kang N, Walther T, Tian XL, Bohlender J, Fukamizu A, Ganten D, Bader M (2002) Reduced hypertension-induced end-organ damage in mice lacking cardiac and renal angiotensinogen synthesis. J Mol Med., 80:359–366

    PubMed  CAS  Google Scholar 

  • Kantachuvesiri S, Fleming S, Peters J, Peters B, Brooker G, Lammie AG, McGrath I, Kotelevtsev Y, Mullins JJ (2001) Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease. J Biol Chem 276:36727–36733

    PubMed  CAS  Google Scholar 

  • Kedzierski RM, Yanagisawa M (2001) Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol 41:851–876

    PubMed  CAS  Google Scholar 

  • Kessler SP, Gomos JB, Scheidemantel TS, Rowe TM, Smith HL, Sen GC (2002) The germinal isozyme of angiotensin-converting enzyme can substitute for the somatic isozyme in maintaining normal renal structure and functions. J Biol Chem 277:4271–4276

    PubMed  CAS  Google Scholar 

  • Kessler SP, Rowe TM, Gomos JB, Kessler PM, Sen GC (2000) Physiological non-equivalence of the two isoforms of angiotensin-converting enzyme. J Biol Chem 275:26259–26264

    PubMed  CAS  Google Scholar 

  • Kim H-S, Krege JH, Kluckman KD, Hagaman JR, Hodgin JB, Best CF, Jennette JC, Coffman TM, Maeda N, Smithies O (1995) Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci USA 92:2735–2739

    PubMed  CAS  Google Scholar 

  • Kimura S, Mullins JJ, Bunnemann B, Metzger R, Hilgenfeldt U, Zimmermann F, Jacob H, Fuxe K, Ganten D, Kaling M (1992) High blood pressure in transgenic mice carrying the rat angiotensinogen gene. EMBO J 11:821–827

    PubMed  CAS  Google Scholar 

  • Kistner A, Gossen M, Zimmermann F, Jerecic J, Ullmer C, Lubbert H, Bujard H (1996) Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci USA 93:10933–10938

    PubMed  CAS  Google Scholar 

  • Krege JH, John SW, Langenbach LL, Hodgin JB, Hagaman JR, Bachman ES, Jennette JC, O’Brien DA, Smithies O (1995) Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature 375:146–148

    PubMed  CAS  Google Scholar 

  • Krege JH, Kim HS, Moyer JS, Jennette JC, Peng L, Hiller SK, Smithies O (1997) Angiotensin-converting enzyme gene mutations, blood pressures, and cardiovascular homeostasis. Hypertension 29:150–157

    PubMed  CAS  Google Scholar 

  • Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, Oda H, Kuwaki T, Cao W-H, Kamada N, Jishage K, Ouchi Y, Azuma S, Toyoda Y, Ishikawa T, Kumada M, Yazaki Y (1994) Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 368:703–710

    PubMed  CAS  Google Scholar 

  • Lazartigues E, Dunlay SM, Loihl AK, Sinnayah P, Lang JA, Espelund JJ, Sigmund CD, Davisson RL (2002) Brain-selective overexpression of angiotensin (AT1) receptors causes enhanced cardiovascular sensitivity in transgenic mice. Circ Res 90:617–624

    PubMed  CAS  Google Scholar 

  • Lemmer B, Mattes A, Böhm M, Ganten D (1993) Circadian blood pressure variation in transgenic hypertensive rats. Hypertension 22:97–101

    PubMed  CAS  Google Scholar 

  • Ling GY, Cao WH, Onodera M, Ju KH, Kurihara H, Kurihara Y, Yazaki Y, Kumada M, Fukuda Y, Kuwaki T (1998) Renal sympathetic nerve activity in mice: comparison between mice and rats and between normal and endothelin-1 deficient mice. Brain Res 808:238–249

    PubMed  CAS  Google Scholar 

  • Lochard N, Silversides DW, van Kats JP, Mercure C, Reudelhuber TL (2003) Brain-specific restoration of angiotensin II corrects renal defects seen in angiotensinogen-deficient mice. J Biol Chem 278:2184–2189

    PubMed  CAS  Google Scholar 

  • Lopez MJ, Garbers DL, Kuhn M (1997) The guanylyl cyclase-deficient mouse defines differential pathways of natriuretic peptide signaling. J Biol Chem 272:23064–23068

    PubMed  CAS  Google Scholar 

  • Lopez MJ, Wong SKF, Kishimoto I, Dubois S, Mach V, Friesen J, Garbers DL, Beuve A (1995) Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature 378:65–68

    PubMed  CAS  Google Scholar 

  • Lu B, Figini M, Emanueli C, Geppetti P, Grady EF, Gerard NP, Ansell J, Payan DG, Gerard C, Bunnett N (1997) The control of microvascular permeability and blood pressure by neutral endopeptidase. Nat Med 3:904–907

    PubMed  CAS  Google Scholar 

  • Lu JT, Son YJ, Lee J, Jetton TL, Shiota M, Moscoso L, Niswender KD, Loewy AD, Magnuson MA, Sanes JR, Emeson RB (1999) Mice lacking alpha-calcitonin gene-related peptide exhibit normal cardiovascular regulation and neuromuscular development. Mol Cell Neurosci 14:99–120

    PubMed  CAS  Google Scholar 

  • Luft FC, Mervaala E, Müller DN, Gross V, Schmidt F, Park JK, Schmitz C, Lippoldt A, Breu V, Dechend R, Dragun D, Schneider W, Ganten D, Haller H (1999) Hypertension-induced end-organ damage: A new transgenic approach to an old problem. Hypertension 33:212–218

    PubMed  CAS  Google Scholar 

  • Madeddu P, Varoni MV, Palomba D, Emanueli C, Demontis MP, Glorioso N, Dessi Fulgheri P, Sarzani R, Anania V (1997) Cardiovascular phenotype of a mouse strain with disruption of bradykinin B2-receptor gene. Circulation 96:3570–3578

    PubMed  CAS  Google Scholar 

  • Masaki H, Kurihara H, Yamaki A, Inomata N, Nozawa Y, Mori Y, Murasawa S, Kizima K, Maruyama K, Horiuchi M, Dzau VJ, Takahashi H, Iwasaka T, Inada M, Matsubara H (1998) Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects. J Clin Invest 101:527–535

    PubMed  CAS  Google Scholar 

  • Massiera F, Bloch-Faure M, Ceiler D, Murakami K, Fukamizu A, Gasc JM, QuignardBoulange A, Negrel R, Ailhaud G, Seydoux J, Meneton P, Teboul M (2001) Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. FASEB J 15:2727–2729

    PubMed  CAS  Google Scholar 

  • Matsukawa N, Grzesik WJ, Takahashi N, Pandey KN, Pang S, Yamauchi M, Smithies O (1999) The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc Natl Acad Sci USA 96:7403–7408

    PubMed  CAS  Google Scholar 

  • Matsusaka T, Kon V, Takaya J, Katori H, Chen X, Miyazaki J, Homma T, Fogo A, Ichikawa I (2000) Dual renin gene targeting by Cre-mediated interchromosomal recombination. Genomics 64:127–131

    PubMed  CAS  Google Scholar 

  • Matsusaka T, Nishimura H, Utsunomiya H, Kakuchi J, Niimura F, Inagami T, Fogo A, Ichikawa I (1996) Chimeric mice carrying’ regional’ targeted deletion of the angiotensin type 1a receptor gene. Evidence against the role for local angiotensin in the in vivo feedback regulation of renin synthesis in juxtaglomerular cells. J Clin Invest 98:1867–1877

    PubMed  CAS  Google Scholar 

  • Mazzolai L, Nussberger J, Aubert JF, Brunner DB, Gabbiani G, Brunner HR, Pedrazzini T (1998) Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system. Hypertension 31:1324–1330

    PubMed  CAS  Google Scholar 

  • Mazzolai L, Pedrazzini T, Nicoud F, Gabbiani G, Brunner HR, Nussberger J (2000) Increased cardiac angiotensin II levels induce right and left ventricular hypertrophy in normotensive mice. Hypertension 35:985–991

    PubMed  CAS  Google Scholar 

  • Meneton P, Bloch-Faure M, Hagege AA, Ruetten H, Huang W, Bergaya S, Ceiler D, Gehring D, Martins I, Salmon G, Boulanger CM, Nussberger J, Crozatier B, Gasc JM, Heudes D, Bruneval P, Doetschman T, Menard J, Alhenc-Gelas F (2001) Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice. Proc Natl Acad Sci USA 98:2634–2639

    PubMed  CAS  Google Scholar 

  • Merrill DC, Thompson MW, Carney CL, Granwehr BP, Schlager G, Robillard JE, Sigmund CD (1996) Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes. J Clin Invest 97:1047–1055

    PubMed  CAS  Google Scholar 

  • Mervaala EM, Müller DN, Park JK, Schmidt F, Lohn M, Breu V, Dragun D, Ganten D, Haller H, Luft FC (1999) Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension. Hypertension 33:389–395

    PubMed  CAS  Google Scholar 

  • Methot D, Lapointe MC, Touyz RM, Yang XP, Carretero OA, Deschepper CF, Schiffrin EL, Thibault G, Reudelhuber TL (1997) Tissue targeting of angiotensin peptides. J Biol Chem 272:12994–12999

    PubMed  CAS  Google Scholar 

  • Milia AF, Gross V, Plehm R, Silva JA, Jr., Bader M, Luft FC (2001) Normal blood pressure and renal function in mice lacking the bradykinin B(2) receptor. Hypertension 37:1473–1479

    PubMed  CAS  Google Scholar 

  • Monti J, Schinke M, Böhm M, Ganten D, Bader M, Bricca G (2001) Glial angiotensinogen regulates brain angiotensin II receptors in transgenic rats TGR(ASrAOGEN) Am J Physiol Regul Integr Comp Physiol 280: R233–R240

    PubMed  CAS  Google Scholar 

  • Morimoto S, Cassell MD, Beltz TG, Johnson AK, Davisson RL, Sigmund CD (2001) Elevated blood pressure in transgenic mice with brain-specific expression of human angiotensinogen driven by the glial fibrillary acidic protein promoter. Circ Res 89:365–372

    PubMed  CAS  Google Scholar 

  • Morimoto S, Cassell MD, Sigmund CD (2002) The brain renin-angiotensin system in transgenic mice carrying a highly regulated human renin transgene. Circ Res 90:80–86

    PubMed  CAS  Google Scholar 

  • Mullins JJ, Peters J, Ganten D (1990) Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 344:541–544

    PubMed  CAS  Google Scholar 

  • Niimura F, Labosky PA, Kakuchi J, Okubo S, Yoshida H, Oikawa T, Ichiki T, Naftilan AJ, Fogo A, Inagami T, Hogan BLM, Ichikawa I (1995) Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation. J Clin Invest 96:2947–2954

    PubMed  CAS  Google Scholar 

  • Ogawa Y, Itoh H, Tamura N, Suga S, Yoshimasa T, Uehira M, Matsuda S, Shiono S, Nishimoto H, Nakao K (1994) Molecular cloning of the complementary DNA and gene that encode mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene. J Clin Invest 93:1911–1921

    PubMed  CAS  Google Scholar 

  • Oh-hashi Y, Shindo T, Kurihara Y, Imai T, Wang Y, Morita H, Imai Y, Kayaba Y, Nishimatsu H, Suematsu Y, Hirata Y, Yazaki Y, Nagai R, Kuwaki T, Kurihara H (2001) Elevated sympathetic nervous activity in mice deficient in alphaCGRP. Circ Res 89:983–990

    PubMed  CAS  Google Scholar 

  • Ohkubo H, Kawakami H, Kakehi Y, Takumi T, Arai H, Yokota Y, Iwai M, Tanabe Y, Masu M, Hata J, Iwao H, Okamoto H, Yokoyama M, Nomura T, Katsuki M, Nakanishi S (1990) Generation of transgenic mice with elevated blood pressure by introduction of the rat renin and angiotensinogen genes. Proc Natl Acad Sci USA 87:5153–5157

    PubMed  CAS  Google Scholar 

  • Ohuchi T, Kuwaki T, Ling GY, Dewit D, Ju KH, Onodera M, Cao WH, Yanagisawa M, Kumada M (1999) Elevation of blood pressure by genetic and pharmacological disruption of the ETB receptor in mice. Am J Physiol 276: R1071–R1077

    PubMed  CAS  Google Scholar 

  • Oliver PM, John SW, Purdy KE, Kim R, Maeda N, Goy MF, Smithies O (1998) Natriuretic peptide receptor 1 expression influences blood pressures of mice in a dose-dependent manner. Proc Natl Acad Sci USA 95:2547–2551

    PubMed  CAS  Google Scholar 

  • Oliver WJ, Gross F (1966) Unique specificity of mouse angiotensinogen to homologous renin. Proc Soc Exp Biol Med 122:923–926

    PubMed  CAS  Google Scholar 

  • Oliverio MI, Kim HS, Ito M, Le T, Audoly L, Best CF, Hiller S, Kluckman K, Maeda N, Smithies O, Coffman TM (1998b) Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II. Proc Natl Acad Sci USA 95:15496–15501

    PubMed  CAS  Google Scholar 

  • Oliverio MI, Madsen K, Best CF, Ito M, Maeda N, Smithies O, Coffman TM (1998a) Renal growth and development in mice lacking AT1 A receptors for angiotensin II. Am J Physiol 274: F43–F50

    PubMed  CAS  Google Scholar 

  • Paradis P, Dali-Youcef N, Paradis FW, Thibault G, Nemer M (2000) Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci USA 97:931–936

    PubMed  CAS  Google Scholar 

  • Pentz ES, Lopez ML, Kim HS, Carretero O, Smithies O, Gomez RA (2001) Ren1d and Ren2 cooperate to preserve homeostasis: evidence from mice expressing GFP in place of Ren1d. Physiol Genomics 6:45–55

    PubMed  CAS  Google Scholar 

  • Pesquero JB, Araujo RC, Heppenstall PA, Stucky CL, Silva JA, Jr., Walther T, Oliveira SM, Pesquero JL, Paiva AC, Calixto JB, Lewin GR, Bader M (2000) Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors. Proc Natl Acad Sci USA 97:8140–8145

    PubMed  CAS  Google Scholar 

  • Pesquero JB, Bader M (1998) Molecular biology of the kallikrein-kinin system: from structure to function. Braz J Med Biol Res 31:1197–1203

    PubMed  CAS  Google Scholar 

  • Peters J, Munter K, Bader M, Hackenthal E, Mullins JJ, Ganten D (1993) Increased adrenal renin in transgenic hypertensive rats, TGR(mREN2)27, and its regulation by cAMP, angiotensin II, and calcium. J Clin Invest 91:742–747

    PubMed  CAS  Google Scholar 

  • Pinto YM, Bader M, Pesquero JB, Tschöpe C, Scholtens E, Van Gilst WH, Buikema H (2000) Increased kallikrein expression protects against cardiac ischemia. FASEB J 14:1861–1863

    PubMed  CAS  Google Scholar 

  • Rajewsky K, Gu H, Kühn R, Betz UA, Müller W, Roes J, Schwenk F (1996) Conditional gene targeting. J Clin Invest 98:600–603

    PubMed  CAS  Google Scholar 

  • Ramaraj P, Kessler SP, Colmenares C, Sen GC (1998) Selective restoration of male fertility in mice lacking angiotensin-converting enzymes by sperm-specific expression of the testicular isozyme. J Clin Invest 102:371–378

    PubMed  CAS  Google Scholar 

  • Schinke M, Baltatu O, Böhm M, Peters J, Rascher W, Bricca G, Lippoldt A, Ganten D, Bader M (1999) Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen. Proc Natl Acad Sci USA 96:3975–3980

    PubMed  CAS  Google Scholar 

  • Schinke M, Böhm M, Bricca G, Ganten D, Bader M (1996) Permanent inhibition of angiotensinogen synthesis by antisense RNA expression. Hypertension 27:508–513

    PubMed  CAS  Google Scholar 

  • Senanayake P, Moriguchi A, Kumagai H, Ganten D, Ferrario CM, Brosnihan KB (1994) Increased expression of angiotensin peptides in the brain of transgenic hypertensive rats. Peptides 15:919–926

    PubMed  CAS  Google Scholar 

  • Sharp MG, Fettes D, Brooker G, Clark AF, Peters J, Fleming S, Mullins JJ (1996) Targeted inactivation of the Ren-2 gene in mice. Hypertension 28:1126–1131

    PubMed  CAS  Google Scholar 

  • Shindo T, Kurihara H, Maemura K, Kurihara Y, Kuwaki T, Izumida T, Minamino N, Ju KH, Morita H, Oh-hashi Y, Kumada M, Kangawa K, Nagai R, Yazaki Y (2000) Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature. Circulation 101:2309–2316

    PubMed  CAS  Google Scholar 

  • Shindo T, Kurihara Y, Nishimatsu H, Moriyama N, Kakoki M, Wang Y, Imai Y, Ebihara A, Kuwaki T, Ju KH, Minamino N, Kangawa K, Ishikawa T, Fukuda M, Akimoto Y, Kawakami H, Imai T, Morita H, Yazaki Y, Nagai R, Hirata Y, Kurihara H (2001) Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene. Circulation 104:1964–1971

    PubMed  CAS  Google Scholar 

  • Sigmund CD (2001) Genetic manipulation of the renin-angiotensin system: targeted expression of the renin-angiotensin system in the kidney. Am J Hypertens 14:33S–37S

    PubMed  CAS  Google Scholar 

  • Sigmund CD, Jones CA, Kane CM, Wu C, Lang JA, Gross KW (1992) Regulated tissue-and cell-specific expression of the human renin gene in transgenic mice. Circ Res 70:1070–1079

    PubMed  CAS  Google Scholar 

  • Silva JA, Jr., Araujo RC, Baltatu O, Oliveira SM, Tschöpe C, Fink E, Hoffmann S, Plehm R, Chai KX, Chao L, Chao J, Ganten D, Pesquero JB, Bader M (2000) Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. FASEB J 14:1858–1860

    PubMed  CAS  Google Scholar 

  • Sinn PL, Davis DR, Sigmund CD (1999) Highly regulated cell type-restricted expression of human renin in mice containing 140-or 160-kilobase pair P1 phage artificial chromosome transgenes. J Biol Chem 274:35785–35793

    PubMed  CAS  Google Scholar 

  • Siragy HM, Inagami T, Ichiki T, Carey RM (1999) Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci USA 96:6506–6510

    PubMed  CAS  Google Scholar 

  • Steinhelper ME, Cochrane KL, Field LJ (1990) Hypotension in transgenic mice expressing atrial natriuretic factor fusion genes. Hypertension 16:301–307

    PubMed  CAS  Google Scholar 

  • Suganami T, Mukoyama M, Sugawara A, Mori K, Nagae T, Kasahara M, Yahata K, Makino H, Fujinaga Y, Ogawa Y, Tanaka I, Nakao K (2001) Overexpression of brain natriuretic peptide in mice ameliorates immune-mediated renal injury. J Am Soc Nephrol 12:2652–2663

    PubMed  CAS  Google Scholar 

  • Sugaya T, Nishimatsu S, Tanimoto K, Takimoto E, Yamagishi T, Imamura K, Goto S, Imaizumi K, Hisada Y, Otsuka A, Uchida H, Sugiura M, Fukuta K, Fukamizu A, Murakami K (1995) Angiotensin II type 1a receptor-deficient mice with hypotension and hyperreninemia. J Biol Chem 270:18719–18722

    PubMed  CAS  Google Scholar 

  • Sugino H, Ozono R, Kurisu S, Matsuura H, Ishida M, Oshima T, Kambe M, Teranishi Y, Masaki H, Matsubara H (2001) Apoptosis is not increased in myocardium overexpressing type 2 angiotensin II receptor in transgenic mice. Hypertension 37:1394–1398

    PubMed  CAS  Google Scholar 

  • Takahashi S, Fukamizu A, Hasegawa T, Yokoyama M, Nomura T, Katsuki M, Murakami K (1991) Expression of the human angiotensinogen gene in transgenic mice and transfected cells. Biochem Biophys Res Commun 180:1103–1109

    PubMed  CAS  Google Scholar 

  • Takimoto E, Ishida J, Sugiyama F, Horiguchi H, Murakami K, Fukamizu A (1996) Hypertension induced in pregnant mice by placental renin and maternal angiotensinogen. Science 274:995–998

    PubMed  CAS  Google Scholar 

  • Tanaka M, Tsuchida S, Imai T, Fujii N, Miyazaki H, Ichiki T, Naruse M, Inagami T (1999) Vascular response to angiotensin II is exaggerated through an upregulation of AT1 receptor in AT2 knockout mice. Biochem Biophys Res Commun 258:194–198

    PubMed  CAS  Google Scholar 

  • Tanimoto K, Sugiyama F, Goto Y, Ishida J, Takimoto E, Yagami K, Fukamizu A, Murakami K (1994) Angiotensinogen-deficient mice with hypotension. J Biol Chem 269:31334–31337

    PubMed  CAS  Google Scholar 

  • Thompson MW, Smith SB, Sigmund CD (1996) Regulation of human renin mRNA expression and protein release in transgenic mice. Hypertension 28:290–296

    PubMed  CAS  Google Scholar 

  • Tian X-L, Costerousse O, Urata H, Franz W-M, Paul M (1996) A new transgenic rat model overexpressing human angiotensin-converting enzyme in the heart. Hypertension 28:520

    Google Scholar 

  • Tigerstedt R, Bergman PG (1898) Niere und Kreislauf. Arch Physiol 8:223–271

    Google Scholar 

  • Tokita Y, Franco-Saenz R, Mulrow PJ, Ganten D (1994) Effects of nephrectomy and adrenalectomy on the renin-angiotensin system on transgenic rats TGR(mRen2)27. Endocrinology 134:253–257

    PubMed  CAS  Google Scholar 

  • Tsuchida S, Matsusaka T, Chen X, Okubo S, Niimura F, Nishimura H, Fogo A, Utsunomiya H, Inagami T, Ichikawa I (1998) Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes. J Clin Invest 101:755–760

    PubMed  CAS  Google Scholar 

  • Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, Miyazaki M, Nozawa Y, Ozono R, Nagakawa K, Miwa T, Kawada N, Mori Y, Shibasaki Y, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Takahashi H, Iwasaka T (1999) Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest 104:925–935

    PubMed  CAS  Google Scholar 

  • van Kats JP, Methot D, Paradis P, Silversides DW, Reudelhuber TL (2001) Use of a biological peptide pump to study chronic peptide hormone action in transgenic mice. Direct and indirect effects of angiotensin II on the heart. J Biol Chem 276:44012–44017

    PubMed  Google Scholar 

  • Veniant M, Menard J, Bruneval P, Morley S, Gonzales MF, Mullins J (1996) Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver. J Clin Invest 98:1966–1970

    PubMed  CAS  Google Scholar 

  • von Bohlen und Halbach O, Walther T, Bader M, Albrecht D (2000) Interaction between Mas and the angiotensin AT1 receptor in the amygdala. J Neurophysiol 83:2012–2021

    Google Scholar 

  • Walther T, Balschun D, Voigt J-P, Fink H, Zuschratter W, Birchmeier C, Ganten D, Bader M (1998) Sustained lonγ-term potentiation and anxiety in mice lacking the Mas protooncogene. J Biol Chem 273:11867–11873

    PubMed  CAS  Google Scholar 

  • Walther T, Wessel N, Kang N, Sander A, Tschöpe C, Malberg H, Bader M, Voss A (2000) Altered heart rate and blood pressure variability in mice lacking the Mas protooncogene. Braz J Med Biol Res 33:1–9

    PubMed  CAS  Google Scholar 

  • Wang DZ, Chao L, Chao J (1997) Hypotension in transgenic mice overexpressing human bradykinin B2 receptor. Hypertension 29:488–493

    PubMed  CAS  Google Scholar 

  • Wang J, Xiong W, Yang Z, Davis T, Dewey MJ, Chao J, Chao L (1994) Human tissue kalli-krein induces hypotension in transgenic mice. Hypertension 23:236–243

    PubMed  CAS  Google Scholar 

  • Wu F, Yan W, Pan J, Morser J, Wu Q (2002) Processing of Pro-atrial Natriuretic Peptide by Corin in Cardiac Myocytes. J Biol Chem 277:16900–16905

    PubMed  CAS  Google Scholar 

  • Yan W, Wu F, Morser J, Wu Q (2000) Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme. Proc Natl Acad Sci USA 97:8525–8529

    PubMed  CAS  Google Scholar 

  • Yanagisawa H, Yanagisawa M, Kapur RP, Richardson JA, Williams SC, Clouthier DE, de Wit D, Emoto N, Hammer RE (1998) Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125:825–836

    PubMed  CAS  Google Scholar 

  • Yanai K, Saito T, Kakinuma Y, Kon Y, Hirota K, Taniguchi-Yanai K, Nishijo N, Shigematsu Y, Horiguchi H, Kasuya Y, Sugiyama F, Yagami K, Murakami K, Fukamizu A (2000) Renin-dependent cardiovascular functions and renin-independent blood-brain barrier functions revealed by renin-deficient mice. J Biol Chem 275:5–8

    PubMed  CAS  Google Scholar 

  • Yang G, Merrill DC, Thompson MW, Robillard JE, Sigmund CD (1994) Functional expression of the human angiotensinogen gene in transgenic mice. J Biol Chem 269:32497–32502

    PubMed  CAS  Google Scholar 

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  1. Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13092, Berlin-Buch, Germany

    M. Bader

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  1. Pharmakologisches Institut, Universität Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany

    Stefan Offermanns

  2. Institut für Pharmakologie und Toxikologie der Universität, Versbacher Straße 9, 97078, Germany

    Lutz Hein

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Bader, M. (2004). Renin-Angiotensin System/Blood Pressure Control. In: Offermanns, S., Hein, L. (eds) Transgenic Models in Pharmacology. Handbook of Experimental Pharmacology, vol 159. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18934-0_13

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  • DOI: https://doi.org/10.1007/978-3-642-18934-0_13

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