Abstract
Angiotensin (Ang) II is not only generated in the circulation by renin and angiotensin-converting enzyme (ACE) but also is produced locally in numerous organs including kidney, vessels, heart, adrenal gland, eye, testis, and brain. Furthermore, widely distributed mast cells have been shown to be a production site. Local Ang II production process is commonly termed the result of a “tissue” renin–angiotensin system (RAS). Because pharmacological experiments do not easily allow targeting of specific tissues, many novel findings about the functional importance of tissue RAS have been collected from transgenic rodent models. These animals either overexpress or lack RAS components in specific tissues and thereby elucidate their local functions. The data to date show that in most tissues local RAS amplify the actions of circulating Ang II with important implications for physiology and pathophysiology of cardiovascular diseases. This review summarizes the recent findings on the importance of tissue RAS in the most relevant cardiovascular organs.
Similar content being viewed by others
Reference
Tigerstedt R, Bergman PG (1898) Niere und Kreislauf. Skand Arch Physiol 8:223–271
Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ (2000) A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275:33238–33243
Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S (2000) A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 87:E1–E9
Santos RA, Simoes e Silva AC, Maric C, Silva DMR, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SVB, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T (2003) Angiotensin-(1-7) is an endogenous ligand for the G-protein coupled receptor Mas. Proc Natl Acad Sci U S A 100:8258–8263
Santos RA, Ferreira AJ (2007) Angiotensin-(1-7) and the renin–angiotensin system. Curr Opin Nephrol Hypertens 16:122–128
Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD (2002) Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109:1417–1427
Burckle C, Bader M (2006) Prorenin and its ancient receptor. Hypertension 48:549–551
Ferguson RK, Turini GA, Brunner HR, Gavras H, McKinstry DN (1977) A specific orally active inhibitor of angiotensin-converting enzyme in man. Lancet 1:775–778
Wong PC, Barnes TB, Chiu AT, Christ DD, Duncia JV, Herblin WF, Timmermans PBMWM (1991) Losartan (DuP 753), an orally active nonpeptide angiotensin II receptor antagonist. Cardiovasc Drug Rev 9:317–339
Staessen JA, Li Y, Richart T (2006) Oral renin inhibitors. Lancet 368:1449–1456
Bader M, Peters J, Baltatu O, Müller DN, Luft FC, Ganten D (2001) Tissue renin–angiotensin systems: new insights from experimental animal models in hypertension research. J Mol Med 79:76–102
Sakai K, Sigmund CD (2005) Molecular evidence of tissue renin–angiotensin systems: a focus on the brain. Curr Hypertens Rep 7:135–140
Fleming I, Kohlstedt K, Busse R (2006) The tissue renin–angiotensin system and intracellular signalling. Curr Opin Nephrol Hypertens 15:8–13
Paul M, Poyan MA, Kreutz R (2006) Physiology of local renin–angiotensin systems. Physiol Rev 86:747–803
Gomez RA, Lynch KR, Chevalier RL, Everett AD, Johns DW, Wilfong N, Peach MJ, Carey RM (1988) Renin and angiotensinogen gene expression and intrarenal renin distribution during ACE inhibition. Am J Physiol 254:900–906
Schulz WW, Hagler HK, Buja LM, Erdos EG (1988) Ultrastructural localization of angiotensin I-converting enzyme (EC 3.4.15.1) and neutral metalloendopeptidase (EC 3.4.24.11) in the proximal tubule of the human kidney. Lab Invest 59:789–797
Moe OW, Ujiie K, Star RA, Miller RT, Widell J, Alpern RJ, Henrich WL (1993) Renin expression in renal proximal tubule. J Clin Invest 91:774–779
Campbell DJ, Lawrence AC, Towrie A, Kladis A, Valentijn AJ (1991) Differential regulation of angiotensin peptide levels in plasma and kidney of the rat. Hypertension 18:763–773
Navar LG, Harrison Bernard LM, Imig JD, Wang CT, Cervenka L, Mitchell KD (1999) Intrarenal angiotensin II generation and renal effects of AT(1) receptor blockade. J Am Soc Nephrol 10:S266–S272
Kobori H, Ozawa Y, Satou R, Katsurada A, Miyata K, Ohashi N, Hase N, Suzaki Y, Sigmund CD, Navar LG (2007) Kidney-specific enhancement of ANG II stimulates endogenous intrarenal angiotensinogen in gene-targeted mice. Am J Physiol Renal Physiol 293:F938–F945
Matsusaka T, Miyazaki Y, Ichikawa I (2002) The renin angiotensin system and kidney development. Annu Rev Physiol 64:551–561
Crowley SD, Gurley SB, Oliverio MI, Pazmino AK, Griffiths R, Flannery PJ, Spurney RF, Kim HS, Smithies O, Le TH, Coffman TM (2005) Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin–angiotensin system. J Clin Invest 115:1092–1099
Crowley SD, Gurley SB, Herrera MJ, Ruiz P, Griffiths R, Kumar AP, Kim HS, Smithies O, Le TH, Coffman TM (2006) Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci U S A 103:17985–17990
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
Lavoie JL, Lake-Bruse KD, Sigmund CD (2004) Increased blood pressure in transgenic mice expressing both human renin and angiotensinogen in the renal proximal tubule. Am J Physiol Renal Physiol 286:F965–F971
Sachetelli S, Liu Q, Zhang SL, Liu F, Hsieh TJ, Brezniceanu ML, Guo DF, Filep JG, Ingelfinger JR, Sigmund CD, Hamet P, Chan JS (2006) RAS blockade decreases blood pressure and proteinuria in transgenic mice overexpressing rat angiotensinogen gene in the kidney. Kidney Int 69:1016–1023
Ganten D, Wagner J, Zeh K, Bader M, Michel JB, 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 U S A 89:7806–7810
Muller DN, Shagdarsuren E, Park JK, Dechend R, Mervaala E, Hampich F, Fiebeler A, Ju X, Finckenberg P, Theuer J, Viedt C, Kreuzer J, Heidecke H, Haller H, Zenke M, Luft FC (2002) Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am J Pathol 161:1679–1693
Park JK, Fischer R, Dechend R, Shagdarsuren E, Gapeljuk A, Wellner M, Meiners S, Gratze P, Al Saadi N, Feldt S, Fiebeler A, Madwed JB, Schirdewan A, Haller H, Luft FC, Muller DN (2007) p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. Hypertension 49:481–489
Ichihara A, Kaneshiro Y, Takemitsu T, Sakoda M, Nakagawa T, Nishiyama A, Kawachi H, Shimizu F, Inagami T (2006) Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage. J Am Soc Nephrol 17:2495–2503
Ichihara A, Hayashi M, Kaneshiro Y, Suzuki F, Nakagawa T, Tada Y, Koura Y, Nishiyama A, Okada H, Uddin MN, Nabi AH, Ishida Y, Inagami T, Saruta T (2004) Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin. J Clin Invest 114:1128–1135
Bader M (2007) The second life of the (Pro)renin receptor. J Renin Ang Ald System 8:205–208
Ganten D, Hayduk K, Brecht HM, Boucher R, Genest J (1970) Evidence of renin release or production in splanchnic territory. Nature 226:551–552
Müller DN, Hilgers KF, Bohlender J, Lippoldt A, Wagner J, Fischli W, Ganten D, Mann JFE, Luft FC (1995) Effects of human renin in the vasculature of rats transgenic for human angiotensinogen. Hypertension 26:272–278
Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG (2007) Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 204:2449–2460
Alenina N, Xu P, Rentzsch B, Bader M (2008) Genetically altered animal models for Mas and angiotensin-(1-7). Exp Physiol (in press)
Burckle C, Danser AHJ, Müller DN, Garrelds IM, Gasc J-M, Plehm R, Peters J, Bader M, Nguyen G (2006) Elevated blood pressure and heart rate in human renin receptor transgenic rats. Hypertension 47:552–556
Batenburg WW, Krop M, Garrelds IM, de Vries R, de Bruin RJA, Burckle C, Mueller DN, Bader M, Nguyen G, Danser AHJ (2007) Prorenin is the endogenous agonist of the (pro)renin receptor. Binding kinetics of renin and prorenin in rat vascular smooth muscle cells overexpressing the human (pro)renin receptor. J Hypertens 25:2441–2453
Sampaio WO, Henrique dC, Santos RA, Schiffrin EL, Touyz RM (2007) Angiotensin-(1–7) counterregulates angiotensin II signaling in human endothelial cells. Hypertension 50:1093–1098
Xu P, Goncalves ACC, Todiras M, Rabelo LA, Sampaio WO, Moura MM, Santos SS, Luft FC, Bader M, Gross V, Alenina N, Santos RA (2008) Endothelial dysfunction and elevated blood pressure in Mas gene-deleted mice. Hypertension 51:574–580
Ramchandran R, Takezako T, Saad Y, Stull L, Fink B, Yamada H, Dikalov S, Harrison DG, Moravec C, Karnik SS (2006) Angiotensinergic stimulation of vascular endothelium in mice causes hypotension, bradycardia, and attenuated angiotensin response. Proc Natl Acad Sci U S A 103:19087–19092
Lindpaintner K, Jin M, Wilhelm MJ, Suzuki F, Linz W, Schoelkens BA, Ganten D (1988) Intracardiac generation of angiotensin and its physiologic role. Circulation 77(suppl 1):I–18–I-23
Dzau VJ (1987) Implications of local angiotensin production in cardiovascular physiology and pharmacology. Am J Cardiol 59:59A–65A
Danser AH, van Kats JP, Admiraal PJ, Derkx FH, Lamers JM, Verdouw PD, Saxena PR, Schalekamp MA (1994) Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis. Hypertension 24:37–48
Peters J, Farrenkopf R, Clausmeyer S, Zimmer J, Kantachuvesiri S, Sharp MG, Mullins JJ (2002) Functional significance of prorenin internalization in the rat heart. Circ Res 90:1135–1141
Mackins CJ, Kano S, Seyedi N, Schafer U, Reid AC, Machida T, Silver RB, Levi R (2006) Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest 116:1063–1070
Gill GN, Ill CR, Simonian MH (1977) Angiotensin stimulation of bovine adrenocortical cell growth. Proc Natl Acad Sci U S A 74:5569–5573
Schelling P, Ganten D, Speck G, Fischer H (1979) Effects of angiotensin II and angiotensin II antagonist saralasin on cell growth and renin in 3T3 and SV3T3 cells. J Cell Physiol 98:503–514
Senbonmatsu T, Ichihara S, Price E Jr., Gaffney FA, Inagami T (2000) Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest 106:R25–R29
Reudelhuber TL, Bernstein KE, Delafontaine P (2007) Is angiotensin II a direct mediator of left ventricular hypertrophy? Time for another look. Hypertension 49:1196–1201
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
Tian XL, Pinto YM, Costerousse O, Franz WM, Lippoldt A, Hoffmann S, Unger T, Paul M (2004) Over-expression of angiotensin converting enzyme-1 augments cardiac hypertrophy in transgenic rats. Hum Mol Genet 13:1441–1450
Xiao HD, Fuchs S, Campbell DJ, Lewis W, Dudley SC Jr., Kasi VS, Hoit BD, Keshelava G, Zhao H, Capecchi MR, Bernstein KE (2004) Mice with cardiac-restricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death. Am J Pathol 165:1019–1032
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
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 U S A 94:6391–6396
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 U S A 97:931–936
Zhai P, Yamamoto M, Galeotti J, Liu J, Masurekar M, Thaisz J, Irie K, Holle E, Yu X, Kupershmidt S, Roden DM, Wagner T, Yatani A, Vatner DE, Vatner SF, Sadoshima J (2005) Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice. J Clin Invest 115:3045–3056
Zhai P, Galeotti J, Liu J, Holle E, Yu X, Wagner T, Sadoshima J (2006) An angiotensin II type 1 receptor mutant lacking epidermal growth factor receptor transactivation does not induce angiotensin II-mediated cardiac hypertrophy. Circ Res 99:528–536
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341:709–717
Connell JM, Mackenzie SM, Freel EM, Fraser R, Davies E (2008) A lifetime of aldosterone excess: long-term consequences of altered regulation of aldosterone production for cardiovascular function. Endocr Rev (in press)
Ganten D, Minnich JL, Granger P, Hayduk K, Brecht HM, Barbeau A, Boucher R, Genest J (1971) Angiotensin-forming enzyme in brain tissue. Science 173:64–65
Phillips MI, Mann JFE, Haebara H, Hoffman WE, Dietz R, Schelling P, Ganten D (1977) Lowering of hypertension by central saralasin in the absence of plasma renin. Nature 270:445–447
Bader M, Ganten D (2002) Editorial: it’s renin in the brain. Circ Res 90:8–10
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
Morimoto S, Cassell MD, Sigmund CD (2002) Glia- and neuron-specific expression of the renin–angiotensin system in brain alters blood pressure, water intake, and salt preference. J Biol Chem 277:33235–33241
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
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 U S A 96:3975–3980
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
Baltatu O, Silva JA Jr., Ganten D, Bader M (2000) The brain renin–angiotensin system modulates angiotensin II-induced hypertension and cardiac hypertrophy. Hypertension 35:409–412
Sinnayah P, Lazartigues E, Sakai K, Sharma RV, Sigmund CD, Davisson RL (2006) Genetic ablation of angiotensinogen in the subfornical organ of the brain prevents the central angiotensinergic pressor response. Circ Res 99:1125–1131
Sakai K, Agassandian K, Morimoto S, Sinnayah P, Cassell MD, Davisson RL, Sigmund CD (2007) Local production of angiotensin II in the subfornical organ causes elevated drinking. J Clin Invest 117:1088–1095
Ryan JW (1967) Renin-like enzyme in the adrenal gland. Science 158:1589–1590
Ganten D, Ganten U, Kubo S, Granger P, Nowaczynski W, Boucher R, Genest J (1974) Influence of sodium, potassium and pituitary hormones on iso-renin in rat adrenal gland. Am J Physiol 227:224–229
Jones CA, Sigmund CD, McGowan RA, Kane-Haas CM, Gross KW (1990) Expression of murine renin genes during fetal development. Mol Endocrinol 4:375–383
Naruse M, Inagami T (1982) Markedly elevated specific renin levels in the adrenal gland in genetically hypertensive rats. Proc Natl Acad Sci U S A 79:3295–3299
Mullins JJ, Peters J, Ganten D (1990) Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 344:541–544
Sander M, Bader M, Djavidani B, Maser Gluth C, Vecsei P, Mullins J, Ganten D, Peters J (1992) The role of the adrenal gland in hypertensive transgenic rat TGR(mREN2)27. Endocrinology 131:807–814
Bader M, Ganten D (2000) Regulation of renin: new evidence from cultured cells and genetically modified mice. J Mol Med 78:130–139
Clausmeyer S, Stürzebecher R, Peters J (1999) An alternative transcript of the rat renin gene can result in a truncated prorenin that is transported into adrenal mitochondria. Circ Res 84:337–344
Peters J, Wanka H, Peters B, Hoffmann S (2008) A renin transcript lacking exon 1 encodes for a non secretory intracellular renin that increases aldosterone production in transgenic rats. J Cell Mol Med (in press)
Peters J, Münter 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
Sequeira Lopez ML, Pentz ES, Nomasa T, Smithies O, Gomez RA (2004) Renin cells are precursors for multiple cell types that switch to the renin phenotype when homeostasis is threatened. Dev Cell 6:719–728
Otis M, Campbell S, Payet MD, Gallo-Payet N (2007) The growth-promoting effects of angiotensin II in adrenal glomerulosa cells: an interactive tale. Mol Cell Endocrinol 273:1–5
Acknowledgment
The Deutsche Forschungsgemeinschaft supported the work of the authors. We thank Friedrich Luft for critical reading of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bader, M., Ganten, D. Update on tissue renin–angiotensin systems. J Mol Med 86, 615–621 (2008). https://doi.org/10.1007/s00109-008-0336-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-008-0336-0