madman
Super Moderator
FIGURE 1 Schematic representing renin angiotensin system (RAS) metabolic pathway components and their main functions. RAS pathway consists of two main axis; ACE/AngI/AngII/AT1R axis and ACE2/Ang 1–7/MasR axis. Local RAS components regulate diverse functions in vital organs such as kidneys, heart, bone marrow, immune system, testis, and brain. Renin cleaves angiotensinogen to produce angiotensin I (Ang I). Ang I is then cleaved byangiotensin converting enzyme (ACE) to produce an active octapeptide angiotensin II (Ang II). Ang II binds to activate a member of G‐protein‐coupled receptor superfamily protein angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) to induce its downstream effects. Ang I can be converted to Ang 1–9 and a heptapeptide Ang 1–7 by angiotensin I converting enzyme 2 (ACE2). ACE2 can directly convert Ang II to produce Ang 1–7. Ang 1–7 binds to Mas R—class I seven‐transmembrane G‐protein‐coupled receptor mediating the downstream effects of Ang 1–7. NEP, neutral endopeptidase; PEP, prolyl endopeptidase. [Color figure can be viewed at wileyonlinelibrary.com]
Abstract
The renin‐angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS‐inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.
| INTRODUCTION
The discovery of the circulating renin‐angiotensin system (RAS) began in 1898 with findings made by noted physiologist Robert Tigerstedt and his student Per Bergman.1 In studying the effects of renal extracts on arterial pressure, they identified a vasoconstricting hormone they accordingly named renin. At the University of Michigan Regional Conference on the Basic Mechanisms of Arterial Hypertension in 1957, researchers determined that renin's substrate would be known as angiotensinogen and its final product as angiotensin.2 Since then, several studies have been conducted to identify the different enzymes and substrates in this pathway, as well as their role in hypertension. This led to the discovery of the classical RAS pathway involving the aforementioned players. As studies progressed, a secondary, nonclassical RAS axis was identified. In the year 2000, both Donoghue et al. and Tipnis et al. independently cloned a homolog of ACE known as angiotensin‐converting enzyme 2 (ACE2).3,4 In addition to ACE2, other tissue‐specific endopeptidases have been discovered, which often cleave angiotensins into other peptides capable of interacting with receptors that counteract the effects of the classical axis.5
As of today, the classical RAS functions are associated with the renal control of blood pressure. When the body detects low blood pressure, juxtaglomerular cells in the kidney produce and cleave prorenin into renin. Renin travels through the bloodstream where it cleaves the substrate angiotensinogen into angiotensin I (AngI). Angiotensinogen is produced by the liver and circulates in blood plasma. Ang I is then converted into angiotensin II (Ang II) by angiotensin‐converting enzyme (ACE), largely in the lungs and kidneys.6 ACE itself is a rather promiscuous enzyme, acting on a number of substrates including the vasodilator bradykinin, neuropeptide substance P, and anti‐inflammatory peptide Ac‐SDKP.7 Ang II then goes on to bind its two main receptor types—AT1 and AT2—and activate several pathways to increase blood pressure. First, it goes onto stimulate the adrenal cortex to release aldosterone which leads to an increase in sodium retention and potassium expulsion, causing a rise in water retention and blood pressure. Ang II also binds to G‐protein‐coupled receptors in arterioles, starting a secondary messenger cascade resulting in vasoconstriction. It also acts on the brain, binding to the hypothalamus and simulating feelings of thirst resulting in higher water intake and therefore higher blood pressure. Still in the brain, Ang II triggers the release of antidiuretic hormone (ADH) front of the posterior pituitary. ADH causes the insertion of aquaporin channels in the collecting ducts of nephrons, causing the reabsorption of more water 6,8 (Figure 1).
However, this is not where the story ends. To get a clearer picture of the system, the nonclassical RAS system cannot be ignored. While the classical RAS is known to increase blood pressure, the nonclassical RAS axis acts to counterbalance it. ACE2, alongside several global and tissue‐specific endopeptidases, are always in homeostasis in a healthy individual.
Ang I and Ang II can be converted into the heptapeptide angiotensin 1–7 (Ang 1–7) and the nonapeptide angiotensin 1–9 (Ang 1–9) via ACE2 and several tissue endopeptidases.9 Ang 1–7 can be converted into a substance known as alamandine. Alamandine can also be generated from peptide Ang A.10 Alamandine then interacts with the mas‐related G protein‐coupled receptor member D (MrgD) to cause several vasodilatory effects, similar to how its precursor Ang 1–7 interacts with its receptor Mas (MasR).11 Although the general idea is that the classical RAS is known to increase blood pressure, and the nonclassical RAS acts to counterbalance it. The alternative axes in the RAS pathway adds to the complexity of the system to make additional druggable targets available to treat cardiovascular and renal diseases.
Understanding the dynamics of classical and nonclassical RAS pathways is important to designing new drugs and strategies to counter the side effects of ACE inhibitors (ACEi). The current review will focus on the functions of various localized RAS components in various organs of human body. We discuss the different components of RAS found in these systems, their tissue‐specific functions, and some potential implications for future medicine.
1.1 | RAS in the kidney
While classical RAS is highly implicated in kidney diseases, alternative RAS has been found to aid the kidney function in maintaining water and solute balance, but more research is required to understand the effect of RAS‐altering drugs on nonclassical RAS response. The nonclassical axis shows promise as a possible treatment of renal maladies.
1.2 | RAS in the heart
In the human heart, up to 80% of Ang II formation is due to chymase, and only about 11% due to ACE.74 There is more variation between other mammalian species.75 Because chymase is the major contributor to Ang II synthesis in the human heart, some suggest the need for chymase inhibitors to control Ang II levels to replace more common RAS antagonists.76 Activation of the classical peptides is implicated in many cardiovascular diseases, while nonclassical axes may help treat such conditions. Most of the active Ang II in the human heart tissue is the result of chymase, not ACE, showing the need for research into alternative pathways.
1.3 | RAS in the brain
Overall, activation of the classical RAS pathway in the brain is associated with the development of several neurodegenerative processes. Signaling of the AT1 and AT2 receptors can contribute to or mitigate the development of neurodegenerative disorders respectively. Activation of the nonclassical ACE2 axis has been shown to help cognitive, behavioral, and neuroinflammatory issues, as well as mental health disorders. Further research could be focused on the mechanistic understanding of these effects.
1.4 | RAS in bone marrow
In erythropoiesis, components of RAS are found in nearly every step of differentiation, with elevated AT1 activity increasing formation of early erythroid progenitors and hematocrit.127 The role of RAS in endothelial progenitor cells (EPCs) is not as straightforward. Acute stimulation of the AT1 receptor can lead to the recruitment of EPCs and resulting proangiogenic effects, suggesting a potential future application in endothelial regeneration.128 However, chronic stimulation of this receptor eventually results in a decrease of both EPC levels and functioning.129,130 Regardless, evidence points to a local RAS being integral to the proliferation, differentiation, and proper function of many cells within the bone marrow, especially when faced with hematopoietic stress.
1.5 | RAS in inflammation and immune response
As a whole, classical RAS, particularly ACE, plays an important role in inflammation and myeloid cell immunity. In contrast, ACE2/Ang 1–7 induces an anti‐inflammatory response. Any attempt to describe how ACE regulates the immune response is complicated by the fact that ACE interacts with a variety of peptides other than Ang II. As discussed, not all the immunomodulatory effects of ACE seem to be mediated by Ang II. Further investigation is needed to establish the role of individual peptides in immune regulation. Thus, understanding the local RAS pathways in the immune system may help in designing new strategies to fight diseases.
1.6 | RAS in male reproduction
Taken together, these studies show that testicular RAS interacts with endocrine hormones to promote proper male development and testosterone levels.193 More research is necessary to determine exactly what pathways link the different components of RAS to these hormones and how. Furthermore, there are increasing findings indicating that tACE is vital for fertility and promoting embryonic development.194 Studying this system may bring insight to such reproductive issues.
2 | CONCLUSION
This review has covered some of the important local tissue RAS and their functions. There are numerous future applications of this knowledge. In the kidneys, a shift in focus from the circulating RAS to local intrarenal RAS, especially the nonclassical axis, may be the grounds for a breakthrough in treatment of CKD. In the heart , manipulating tissue RAS pathways in addition to circulating RAS could be the key to treating persistent cardiovascular diseases. In the brain, the activation of different axes of the RAS can aid in the treatment of aging‐related, neurodegenerative, and mental health disorders. In bone marrow, altering the local RAS may aid in hematopoiesis and endothelial regeneration. The immune response can be boosted or stunted by the inhibition or activation of RAS, bringing into question the treatment of immunocompromised patients or those with chronic immune responses. As for reproduction, the study of RAS may give key insight into solutions for infertility and promoting proper embryonic development.
The study of tissue RAS also necessitates the rethinking of the current usage of drugs affecting the circulating RAS. Nearly one in two adults in the United States suffers from hypertension—that is around 116 million people.195 The most commonly prescribed drugs for this condition are ACEi such as enalapril, lisinopril, and ramipril.196 However, these drugs could have unintended positive or negative consequences on local RAS throughout the body. For example, in the brain, inhibiting ACE may increase ACE2 levels, improving brain function. ACE inhibition may also actually lower the body's immune response, putting into question whether immunocompromised individuals with hypertension should take these drugs or perhaps an alternative such as ARBs. There are currently no official guidelines to say when patients with such conditions should be taking ACEi, ARBs, renin inhibitors, or alternative RAS‐interfering drugs. With the emerging science on how RAS presents in other bodily systems, this must be reevaluated.
Further study of these various tissue RAS is an essential step in medical progress. It highlights both the gaps in our knowledge as well as potential opportunities for the future. Understanding how these tissue systems work in everyday life and how they interact with current therapies/medication is imperative.
Abstract
The renin‐angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS‐inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.
| INTRODUCTION
The discovery of the circulating renin‐angiotensin system (RAS) began in 1898 with findings made by noted physiologist Robert Tigerstedt and his student Per Bergman.1 In studying the effects of renal extracts on arterial pressure, they identified a vasoconstricting hormone they accordingly named renin. At the University of Michigan Regional Conference on the Basic Mechanisms of Arterial Hypertension in 1957, researchers determined that renin's substrate would be known as angiotensinogen and its final product as angiotensin.2 Since then, several studies have been conducted to identify the different enzymes and substrates in this pathway, as well as their role in hypertension. This led to the discovery of the classical RAS pathway involving the aforementioned players. As studies progressed, a secondary, nonclassical RAS axis was identified. In the year 2000, both Donoghue et al. and Tipnis et al. independently cloned a homolog of ACE known as angiotensin‐converting enzyme 2 (ACE2).3,4 In addition to ACE2, other tissue‐specific endopeptidases have been discovered, which often cleave angiotensins into other peptides capable of interacting with receptors that counteract the effects of the classical axis.5
As of today, the classical RAS functions are associated with the renal control of blood pressure. When the body detects low blood pressure, juxtaglomerular cells in the kidney produce and cleave prorenin into renin. Renin travels through the bloodstream where it cleaves the substrate angiotensinogen into angiotensin I (AngI). Angiotensinogen is produced by the liver and circulates in blood plasma. Ang I is then converted into angiotensin II (Ang II) by angiotensin‐converting enzyme (ACE), largely in the lungs and kidneys.6 ACE itself is a rather promiscuous enzyme, acting on a number of substrates including the vasodilator bradykinin, neuropeptide substance P, and anti‐inflammatory peptide Ac‐SDKP.7 Ang II then goes on to bind its two main receptor types—AT1 and AT2—and activate several pathways to increase blood pressure. First, it goes onto stimulate the adrenal cortex to release aldosterone which leads to an increase in sodium retention and potassium expulsion, causing a rise in water retention and blood pressure. Ang II also binds to G‐protein‐coupled receptors in arterioles, starting a secondary messenger cascade resulting in vasoconstriction. It also acts on the brain, binding to the hypothalamus and simulating feelings of thirst resulting in higher water intake and therefore higher blood pressure. Still in the brain, Ang II triggers the release of antidiuretic hormone (ADH) front of the posterior pituitary. ADH causes the insertion of aquaporin channels in the collecting ducts of nephrons, causing the reabsorption of more water 6,8 (Figure 1).
However, this is not where the story ends. To get a clearer picture of the system, the nonclassical RAS system cannot be ignored. While the classical RAS is known to increase blood pressure, the nonclassical RAS axis acts to counterbalance it. ACE2, alongside several global and tissue‐specific endopeptidases, are always in homeostasis in a healthy individual.
Ang I and Ang II can be converted into the heptapeptide angiotensin 1–7 (Ang 1–7) and the nonapeptide angiotensin 1–9 (Ang 1–9) via ACE2 and several tissue endopeptidases.9 Ang 1–7 can be converted into a substance known as alamandine. Alamandine can also be generated from peptide Ang A.10 Alamandine then interacts with the mas‐related G protein‐coupled receptor member D (MrgD) to cause several vasodilatory effects, similar to how its precursor Ang 1–7 interacts with its receptor Mas (MasR).11 Although the general idea is that the classical RAS is known to increase blood pressure, and the nonclassical RAS acts to counterbalance it. The alternative axes in the RAS pathway adds to the complexity of the system to make additional druggable targets available to treat cardiovascular and renal diseases.
Understanding the dynamics of classical and nonclassical RAS pathways is important to designing new drugs and strategies to counter the side effects of ACE inhibitors (ACEi). The current review will focus on the functions of various localized RAS components in various organs of human body. We discuss the different components of RAS found in these systems, their tissue‐specific functions, and some potential implications for future medicine.
1.1 | RAS in the kidney
While classical RAS is highly implicated in kidney diseases, alternative RAS has been found to aid the kidney function in maintaining water and solute balance, but more research is required to understand the effect of RAS‐altering drugs on nonclassical RAS response. The nonclassical axis shows promise as a possible treatment of renal maladies.
1.2 | RAS in the heart
In the human heart, up to 80% of Ang II formation is due to chymase, and only about 11% due to ACE.74 There is more variation between other mammalian species.75 Because chymase is the major contributor to Ang II synthesis in the human heart, some suggest the need for chymase inhibitors to control Ang II levels to replace more common RAS antagonists.76 Activation of the classical peptides is implicated in many cardiovascular diseases, while nonclassical axes may help treat such conditions. Most of the active Ang II in the human heart tissue is the result of chymase, not ACE, showing the need for research into alternative pathways.
1.3 | RAS in the brain
Overall, activation of the classical RAS pathway in the brain is associated with the development of several neurodegenerative processes. Signaling of the AT1 and AT2 receptors can contribute to or mitigate the development of neurodegenerative disorders respectively. Activation of the nonclassical ACE2 axis has been shown to help cognitive, behavioral, and neuroinflammatory issues, as well as mental health disorders. Further research could be focused on the mechanistic understanding of these effects.
1.4 | RAS in bone marrow
In erythropoiesis, components of RAS are found in nearly every step of differentiation, with elevated AT1 activity increasing formation of early erythroid progenitors and hematocrit.127 The role of RAS in endothelial progenitor cells (EPCs) is not as straightforward. Acute stimulation of the AT1 receptor can lead to the recruitment of EPCs and resulting proangiogenic effects, suggesting a potential future application in endothelial regeneration.128 However, chronic stimulation of this receptor eventually results in a decrease of both EPC levels and functioning.129,130 Regardless, evidence points to a local RAS being integral to the proliferation, differentiation, and proper function of many cells within the bone marrow, especially when faced with hematopoietic stress.
1.5 | RAS in inflammation and immune response
As a whole, classical RAS, particularly ACE, plays an important role in inflammation and myeloid cell immunity. In contrast, ACE2/Ang 1–7 induces an anti‐inflammatory response. Any attempt to describe how ACE regulates the immune response is complicated by the fact that ACE interacts with a variety of peptides other than Ang II. As discussed, not all the immunomodulatory effects of ACE seem to be mediated by Ang II. Further investigation is needed to establish the role of individual peptides in immune regulation. Thus, understanding the local RAS pathways in the immune system may help in designing new strategies to fight diseases.
1.6 | RAS in male reproduction
Taken together, these studies show that testicular RAS interacts with endocrine hormones to promote proper male development and testosterone levels.193 More research is necessary to determine exactly what pathways link the different components of RAS to these hormones and how. Furthermore, there are increasing findings indicating that tACE is vital for fertility and promoting embryonic development.194 Studying this system may bring insight to such reproductive issues.
2 | CONCLUSION
This review has covered some of the important local tissue RAS and their functions. There are numerous future applications of this knowledge. In the kidneys, a shift in focus from the circulating RAS to local intrarenal RAS, especially the nonclassical axis, may be the grounds for a breakthrough in treatment of CKD. In the heart , manipulating tissue RAS pathways in addition to circulating RAS could be the key to treating persistent cardiovascular diseases. In the brain, the activation of different axes of the RAS can aid in the treatment of aging‐related, neurodegenerative, and mental health disorders. In bone marrow, altering the local RAS may aid in hematopoiesis and endothelial regeneration. The immune response can be boosted or stunted by the inhibition or activation of RAS, bringing into question the treatment of immunocompromised patients or those with chronic immune responses. As for reproduction, the study of RAS may give key insight into solutions for infertility and promoting proper embryonic development.
The study of tissue RAS also necessitates the rethinking of the current usage of drugs affecting the circulating RAS. Nearly one in two adults in the United States suffers from hypertension—that is around 116 million people.195 The most commonly prescribed drugs for this condition are ACEi such as enalapril, lisinopril, and ramipril.196 However, these drugs could have unintended positive or negative consequences on local RAS throughout the body. For example, in the brain, inhibiting ACE may increase ACE2 levels, improving brain function. ACE inhibition may also actually lower the body's immune response, putting into question whether immunocompromised individuals with hypertension should take these drugs or perhaps an alternative such as ARBs. There are currently no official guidelines to say when patients with such conditions should be taking ACEi, ARBs, renin inhibitors, or alternative RAS‐interfering drugs. With the emerging science on how RAS presents in other bodily systems, this must be reevaluated.
Further study of these various tissue RAS is an essential step in medical progress. It highlights both the gaps in our knowledge as well as potential opportunities for the future. Understanding how these tissue systems work in everyday life and how they interact with current therapies/medication is imperative.
