Elsevier

Peptides

Volume 32, Issue 7, July 2011, Pages 1551-1565
Peptides

Review
New insights and perspectives on intrarenal renin-angiotensin system: Focus on intracrine/intracellular angiotensin II

https://doi.org/10.1016/j.peptides.2011.05.012Get rights and content

Abstract

Although renin, the rate-limiting enzyme of the renin-angiotensin system (RAS), was first discovered by Robert Tigerstedt and Bergman more than a century ago, the research on the RAS still remains stronger than ever. The RAS, once considered to be an endocrine system, is now widely recognized as dual (circulating and local/tissue) or multiple hormonal systems (endocrine, paracrine and intracrine). In addition to the classical renin/angiotensin I-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor (AT1/AT2) axis, the prorenin/(Pro)renin receptor (PRR)/MAP kinase axis, the ACE2/Ang (1–7)/Mas receptor axis, and the Ang IV/AT4/insulin-regulated aminopeptidase (IRAP) axis have recently been discovered. Furthermore, the roles of the evolving RAS have been extended far beyond blood pressure control, aldosterone synthesis, and body fluid and electrolyte homeostasis. Indeed, novel actions and underlying signaling mechanisms for each member of the RAS in physiology and diseases are continuously uncovered. However, many challenges still remain in the RAS research field despite of more than one century's research effort. It is expected that the research on the expanded RAS will continue to play a prominent role in cardiovascular, renal and hypertension research. The purpose of this article is to review the progress recently being made in the RAS research, with special emphasis on the local RAS in the kidney and the newly discovered prorenin/PRR/MAP kinase axis, the ACE2/Ang (1–7)/Mas receptor axis, the Ang IV/AT4/IRAP axis, and intracrine/intracellular Ang II. The improved knowledge of the expanded RAS will help us better understand how the classical renin/ACE/Ang II/AT1 receptor axis, extracellular and/or intracellular origin, interacts with other novel RAS axes to regulate blood pressure and cardiovascular and kidney function in both physiological and diseased states.

Highlights

► The renin-angiotensin system is now evolving as an endocrine, paracrine and intracrine system. ► The renin/ACE/Ang II/AT1 receptor axis is the most recognized cascade of the entire system. ► The prorenin/(Pro)renin receptor/MAP kinases ERK 1/2 axis is activated in diseased states. ► The ACE2/Ang (1–7) Mas receptor axis opposes the effects induced by Ang II via AT1 receptors.

Introduction

Since renin, the rate-limiting enzyme of the renin-angiotensin system (RAS), was first discovered by Robert Tigerstedt and Bergman more than a century ago [209], the RAS is now well recognized as a dual vasoactive system, acting as both a circulating endocrine system and a local tissue paracrine system [25], [76], [110]. A local RAS has been demonstrated in nearly every target tissues including the kidney, adrenal glands, heart, blood vessels, pancreas, liver, brain, and even adipose tissues. The localization and functional properties of a local RAS in various target tissues have been reviewed elsewhere [12], [29], [40], [61], [65], [116], [235]. The objective of this review therefore focuses solely on the new insights and perspectives on the endocrine, paracrine and intracrine RAS in the kidney. In the kidney, all major components of the RAS, including the precursor angiotensinogen, the rate-limiting enzyme renin and angiotensin I-converting enzyme (ACE), and the receptors for angiotensin II (Ang II), AT1 and AT2, Ang (1–7) and Ang (3–8) have been demonstrated (Fig. 1) [29], [35], [106], [152], [162], [237]. Although there are continuous debates on whether renin and angiotensinogen are synthesized or taken up in tissues other than the juxtaglomerular apparatus (JGA) or hepatocytes, respectively, there is a consensus that the presence of renin, angiotensinogen and ACE in tissues is necessary for local formation of Ang II independent of circulating Ang II. In spite of recent discovery of several new components of the RAS, such as prorenin or (Pro)renin receptor, PRR [167], [168], the second ACE (ACE2) [51], [68], biologically active angiotensin fragments such as Ang (1–7) and Ang (3–8) (Ang IV) [35], [81], and the novel receptors for Ang (1–7), Mas [186], and Ang IV, AT4 [3], Ang II is still and will remain to be the principle effector of the RAS in the kidney and other tissues. Likewise, although five major classes of Ang receptors, AT1a, AT1b and AT2 for Ang II, the Mas receptor for Ang (1–7), and AT4 for Ang IV have been cloned, the AT1 (AT1a) receptor remains to be the principal receptor that mediates the majority of the known actions of Ang II in the kidney [30], [39], [75], [171], [198], [234], [238]. Nevertheless, new progress has indeed been made in several areas during last several years. First, what we have known as the classical RAS for many decades has now expanded to include prorenin/PRR [167], [168] and ACE2 [51], [68] (Fig. 2). Second, there are renewed interests in the physiological and pathophysiological roles of several Ang II metabolites including Ang III, Ang (1–7) and Ang IV [33], [81], [172]. Third, the so-called intracrine/intracellular RAS or Ang II, which was previously considered not to be physiologically important, has been recently shown to have blood pressure-increasing effects in rodents [134], [179]. The critical review or timely update of these new developments in the RAS research may provide new insights and perspectives into both classic and novel roles of the RAS in the physiological regulation of blood pressure, cardiovascular and kidney functions, and in the development of hypertension, cardiovascular and kidney diseases.

Section snippets

Localization and roles of prorenin in the kidney

The molecular biology, structure, biochemistry and the roles of prorenin and (Pro)renin receptors (PRR) in physiology and diseases have been critically reviewed elsewhere [26], [58], [165], [197]. In the current article, only the progress on the kidney- and blood pressure-related prorenin and PRR research is briefly reviewed. The kidney was initially thought to be the only tissue to produce renin in JGA cells. Indeed, renin was found to decrease markedly after the kidneys were removed in humans

Roles of ACE2 in Ang (1–7) formation in the kidney and other tissues

Recently, there has been an explosion of renewed interest in studying the biological, physiological and pathophysiological role of the angiotensin metabolite, Ang (1–7), following the discoveries of ACE2 and the Mas receptor specific for Ang (1–7) [35], [81], [105], [185], [194]. Ang (1–7) is a heptapeptide of the RAS, which may be generated in two different ways. First, a number of enzymes in tissues including neprilysin [EC 3.4.24.11], prolyl oligopeptidase [EC 3.4.24.26], and thimet

Roles of aminopeptidases A and N in Ang IV formation in the kidney and other tissues

Ang (3–8), also termed Ang IV, is another biologically active Ang II fragment that has been a subject of extensive studies during recent years. Ang IV is primarily derived from Ang II or Ang III through the enzymatic actions of aminopeptidases A and N to cleave one or two N terminal amino acids [8], [9]. The Ang IV/AT4 receptors and their biological and pharmacological properties and tissue distribution have been comprehensively reviewed [61]. In the current article, we will focus on the Ang

Overview of the knowledge gap on the roles of intracrine/intracellular Ang II

Angiotensin II is undoubtedly the major effector of the renin/ACE/Ang II/AT1 receptor axis in long-term cardiovascular, renal and blood pressure regulation (Fig. 1, Fig. 2). There is also no doubt that extracellular (circulating and paracrine) Ang II plays the classical roles of Ang II through activation of cell surface GPCRs (Fig. 3) [25], [29], [61], [110], [151], [210], [212]. Thus, no wonder many have assumed that: (1) Ang II only needs to activate cell surface receptors to induce all of

Future perspectives of the evolving endocrine, paracrine and intracrine RAS in cardiovascular, renal and hypertension research

In summary, the great progress has been made in the RAS research field since renin was first discovered by Tigerstedt and Bergman more than a century ago. The RAS, once considered as an endocrine system, is now recognized as dual (circulating and local/tissue) or multiple systems (endocrine, paracrine and intracrine). In addition to the classical renin/ACE/Ang II/Ang II receptor axis, we have now added several new axes to the RAS family, namely the prorenin/PRR/MAPK axis, the ACE2/Ang (1–7)/Mas

Acknowledgements

The authors’ work was supported in part by National Institute of Diabetes, Digestive and Kidney Diseases grants (5RO1DK067299, 2R56DK067299, and 2RO1DK067299), American Society of Nephrology M. James Scherbenske grant, and institutional supports from Henry Ford Health System, Detroit, Michigan and the University of Mississippi Medical Center, Jackson, Mississippi to Dr. Jia L. Zhuo. We sincerely thank all of our past and current collaborators for their expertise and our laboratory

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