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The brain renin–angiotensin system: a diversity of functions and implications for CNS diseases

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Abstract

The classic renin–angiotensin system (RAS) was initially described as a hormone system designed to mediate cardiovascular and body water regulation, with angiotensin II as its major effector. The discovery of an independent local brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins, and specific receptor proteins) significantly expanded the possible physiological and pharmacological functions of this system. This review first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT1, AT2, and AT4 receptor subtypes. Next, we discuss the classic physiologies and behaviors controlled by the RAS including cardiovascular, thirst, and sodium appetite. A final section summarizes non-classic functions and clinical conditions mediated by the brain RAS with focus on memory and Alzheimer’s disease. There is no doubt that the brain RAS is an important component in the development of dementia. It also appears to play a role in normal memory consolidation and retrieval. The presently available anti-dementia drugs are proving to be reasonably ineffective, thus alternative treatment approaches must be developed. At the same time, presently available drugs must be tested for their efficacy to treat newly identified syndromes and diseases connected with the RAS. The list of non-classic physiologies and behaviors is ever increasing in both number and scope, attesting to the multidimensional influences of the RAS. Such diversity in function presents a dilemma for both researchers and clinicians. Namely, the blunting of RAS subsystems in the hopes of combating one constellation of underlying causes and disease symptoms may be counter-balanced by unanticipated and unwanted consequences to another RAS subsystem. For example, the use of angiotensin-converting enzyme inhibitors and AT1 and/or AT2 receptor blockers have shown great promise in the treatment of cardiovascular related pathologies; however, their use could negate the cerebroprotective benefits offered by this system.

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Acknowledgments

Research from our laboratory presented in this review was supported by the Edward E. and Lucille I. Lainge Endowment for Alzheimer’s Research, the Michael J. Fox Foundation, and funds provided for Medical and Biological Research by the State of Washington Initiative Measure No. 171.

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  1. Department of Psychology, Washington State University, P.O. Box 644820, Pullman, WA, 99164-4820, USA

    John W. Wright & Joseph W. Harding

  2. Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, P.O. Box 644820, Pullman, WA, 99164-4820, USA

    John W. Wright & Joseph W. Harding

  3. Programs in Neuroscience and Biotechnology, Washington State University, P.O. Box 646520, Pullman, WA, 99164-6520, USA

    John W. Wright & Joseph W. Harding

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  1. John W. Wright
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Correspondence to John W. Wright.

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This article is published as part of the special issue on Renin–Angiotensin System.

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Wright, J.W., Harding, J.W. The brain renin–angiotensin system: a diversity of functions and implications for CNS diseases. Pflugers Arch - Eur J Physiol 465, 133–151 (2013). https://doi.org/10.1007/s00424-012-1102-2

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  • DOI: https://doi.org/10.1007/s00424-012-1102-2

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