The renin-angiotensin system (RAS) is one of the most important endocrine (tissue-to-tissue), paracrine (cell-to-cell) and intracrine (intracellular/nuclear) humoral systems in the regulation of blood pressure, cardiovascular, and kidney function in health and disease. The RAS has remarkably evolved from the initial discovery of the rate-limiting enzyme renin to a complex biochemical and physiological cascade involving more than a dozen members. Currently, there are up to five axes or pathways identified in the RAS; each has its substrate, enzyme, effector peptide, receptor, and downstream signaling pathways. These include the renin/ACE/ANG II/AT1
receptor, the APA/ANG III/AT2
receptor, the ACE2/ANG (1-7)/Mas receptor, the prorenin/prorenin receptor (PRR), and the ANG IV/AT4
receptor (IRAP) pathways. Accordingly, the roles of the RAS have expanded well beyond the classic endocrine paradigm as a powerful vasoconstrictor, a potent aldosterone stimulator, or a sodium-retaining hormonal system. The goals of this article are to review and discuss the current insights into and new perspectives on the expression, localization, and novel actions of the RAS with a focus in the kidney. Special emphasis will be placed on recently discovered new members of the RAS derived from studies using innovative mutant rats or mice that either overexpress (knockin) or are deficient (knockout) of a particular substrate, enzyme, ANG peptide, or receptor. This new knowledge will help improve our understanding how each of these pathways act directly or indirectly to regulate blood pressure, cardiovascular and kidney function in physiology, and can be targeted to treat hypertension, cardiovascular and renal diseases.
Table of Contents
Localization and Roles of the Renin/ACE/ANG II/AT1
Receptor Axis in the Kidney
Localization and Functional Properties of the ACE2
/ANG (1-7)/Mas Receptor Axis in the Kidney
Localization and Roles of the Prorenin/PRR/MAP Kinases ERK 1/2 Axis in the Kidney
The Localization and Potential Roles of other ANG Peptides or Receptors in the Kidney
About the Author(s)Xiao C. Li
, University of Mississippi Medical CenterJia L. Zhou
, University of Mississippi Medical Center
Jia L. Zhuo, M.D., Ph.D. is Professor of Pharmacology and Toxicology at the University of Mississippi Medical Center. He received his M.D. from Guangxi Medical University, China in 1983, and his Ph.D. in Renal Physiology from the University of Melbourne, Australia in 1990. Dr. Zhuo has a track record of over 25 years of productive and sponsored research on the roles of endocrine, paracrine, and intracrine angiotensin II in the kidney, supported by the National Health and Medical Research Council of Australia (NH&MRC), the American Heart Association, the American Society of Nephrology, and the National Institutes of Health. He has authored over 100 peer-reviewed articles and book chapters, many of them recognized by editorials, cover highlights, and the Faculty of 1000. Dr. Zhuo currently serves as the Chair for the American Physiological Society Physiological Genomics Group, is a permanent member for National Institute of Health/Center for Scientific Review (NIH/CSR)-Hypertension and Microcirculation Study Section, and several NIH/CSR special emphasis panels. He also serves as an Ad Hoc reviewer for the Australian NH&MRC, Chinese Ministry of Educationâ€™s Chang Jiang Scholar Program, and the Danish Council for Independent Research. His research is currently funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of General Medical Sciences (NIGMS).