Tissue renin-angiotensin systems: new insights from experimental animal models in hypertension research

Renin was first isolated in the kidney by Tigerstedt and Bergman over 100 y ears ago. Almost 50 additional years were: necessary to isolate the renin s ubstrate angiotensinogen and to show its cleavage to angiotensin (Ang). Fur ther studies were then needed to demonstrate that Ang I is converted via an angiotensin-converting enzyme to Ang II. The circulating renin-angiotensin system, with blood pressure regulatory and aldosterone stimulatory roles, sen ed well for decades. However 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 attent ion on local Ang II generation and effects. These investigations necessaril y began in the kidney, but quickly moved to other organs including the brai n, heart, adrenal gland, and vessel wall and formed the basis for the conce pt of independent tissue renin-angiotensin systems. Both renin and Ang II h ave even been implicated in intracellular activities. This review presents some selected aspects of the historical development of this concept and sum marizes discoveries relying primarily on animal models which demonstrate th at Ang II is generated locally and acts in tissues as a local peptidergic s ystem. Comprehensiveness in such an endeavor is not possible. We focus larg ely on Work from our own group, not because the work is necessarily worthy of such scrutiny but rather because of our own familiarity With the content s.