Abstract Renin was first isolated in the kidney by Ti- gerstedt and Bergman over 100 years ago. Almost 50 ad- ditional years were necessary to isolate the renin sub- strate angiotensinogen and to show its cleavage to angio- tensin (Ang). Further studies were then needed to dem- onstrate that Ang I is converted via an angiotensin-con- verting enzyme to Ang II. The circulating renin-angio- tensin system, with blood pressure regulatory and aldo- sterone stimulatory roles, served well for decades. How- ever, more recent information on Ang II and its action in terms of cell proliferation, hypertrophy, and hyperplasia as well as immune-modulatory and even intracellular functions, have focused attention on local Ang II genera- tion and effects. These investigations necessarily began in the kidney, but quickly moved to other organs includ- ing the brain, heart, adrenal gland, and vessel wall and formed the basis for the concept of independent tissue renin-angiotensin systems. Both renin and Ang II have even been implicated in intracellular activities. This re- view presents some selected aspects of the historical de- velopment of this concept and summarizes discoveries relying primarily on animal models which demonstrate that Ang II is generated locally and acts in tissues as a local peptidergic system. Comprehensiveness in such an endeavor is not possible. We focus largely on work from our own group, not because the work is necessarily wor- thy of such scrutiny but rather because of our own famil- iarity with the contents. Keywords Renin · Angiotensin · Transgenic rats · Gene targeting Abbreviations ACE: Angiotensin-converting enzyme · Ang: Angiotensin · AOGEN: Angiotensinogen · CNS: Central nervous system · JAK: Janus kinase · MAP: Mitogen-activated protein · NF: Nuclear factor · RAS: Renin-angiotensin system · STAT: Signal transducer and activator of transcription · TGR: Transgenic rat Introduction The renin-angiotensin system (RAS) began in the kidney. Renin was discovered in this organ by Tigerstedt and Bergman 100 years ago [1]. Fifty years later renin’s ac- tion in the circulation was clarified considerably when the structures of angiotensin (Ang) I and Ang II were deter- mined (for an historical account see [2]). A basic schema was developed in which renin is produced by juxtaglom- erular cells in the kidney. Renin serves as a circulating enzyme which splits the renin substrate, angiotensinogen (AOGEN), in the plasma to form the decapeptide Ang I. Ang I is then metabolized further into the octapeptide Ang II via the angiotensin-converting enzyme (ACE). ACE is present at various places (testis for instance) but is primarily an endothelial-bound enzyme with particular- ly high concentrations in the lung. Ang II then serves as a circulating vasopressor substance with various other du- ties such as stimulating the release of aldosterone from the adrenal gland. These effects are transmitted by two main receptors, AT1 and AT2 that were originally defined by discovery of specific ligands and later confirmed by the cloning of two different genes [3, 4, 5]. Most of the known effects of Ang II are attributed to the AT1 recep- tor, which as with the AT2 receptor, belongs to the seven- transmembrane G protein coupled receptor family. In ro- dents two different subtypes of the AT1 receptor have been found, namely AT1A and AT1B [6]. This very serviceable schema served us well for de- cades. However, with additional research, the straightfor- M. Bader ( ✉ ) · O. Baltatu · D.N. Müller · F.C. Luft · D. Ganten Max Delbrück Center for Molecular Medicine and Franz Volhard Clinic, 13092 Berlin-Buch, Germany e-mail: mbader@mdc-berlin.de Tel.: +49-30-94062193, Fax: +49-30-94062110 J. Peters Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany D. Ganten Institute for Clinical Pharmacology, University Clinic Benjamin Franklin, Free University Berlin, 12200 Berlin, Germany J Mol Med (2001) 79:76–102 DOI 10.1007/s001090100210 REVIEW Michael Bader · Jörg Peters · Ovidiu Baltatu Dominik N. Müller · Friedrich C. Luft Detlev Ganten Tissue renin-angiotensin systems: new insights from experimental animal models in hypertension research Received: 1 February 2001 / Accepted: 8 February 2001 / Published online: 9 March 2001 © Springer-Verlag 2001