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Maleki M, kheiry M, vakilian A, mohamadi S, shokri F. The role of the renin-angiotensin system in a model of cisplatin-induced nephrotoxicity: a systematic review. Journal title 2024; 1403 (2)
URL: http://newresearch.medilam.ac.ir/article-1-2492-en.html
URL: http://newresearch.medilam.ac.ir/article-1-2492-en.html
Department of Physiology, School of Medicine, Ilam University of Medical sciences, Ilam, Iran
Abstract: (180 Views)
Renin-angiotensin system (RAS), despite the long history of its discovery, is still one of the research areas to discover
Interference between the components of this system is one of the topics of interest to researchers. The RAS contains different receptors with different vascular responses. In addition to AT1, there are two other receptors. Angiotensin II receptor 2 (AT2) and angiotensin receptor (1-7) (Mas) in RAS are gender-dependent and the role of these receptors is more important in women than in men (1). The activity of the renin-angiotensin system (RAS) is important among vasoactive substances because it reduces renal perfusion and, as a result, hypoxia of the downstream tubulointerstitial tissue with the contraction of the efferent arteriole through the angiotensin type 1 receptor (AT1). Therefore, the role of RAS and its constituent factors or even factors affecting it in the process of renal ischemia-reperfusion has a special role. The AT1 receptor is one of the G protein-coupled receptors (GPCRs) that spans 7 times the width of the membrane. Its G protein is of the Gq type, but it lacks intrinsic tyrosine kinase activity (3). The binding of angiotensin II to this receptor activates phospholipase C (PLC) and causes the accumulation of inositol triphosphate (IP3) and diacylglycerol (DAG). By increasing the intracellular calcium concentration, IP3 causes vascular smooth muscle cell contraction and aldosterone secretion from the adrenal cortical part. DAG activates protein kinase C (PKC) and finally phosphorylates some proteins in this pathway, causing vascular contraction and cell growth. 3).
Kidney plays an important role in regulating arterial pressure and body fluid volume in connection with RAS (4). However, the role of the depressor of this system in regulating kidney function in physiological and disease conditions is not well known (5, 6). Angiotensin II type 2 receptor (AT2) and Mas receptor are part of RAS depressor arm (5, 6). Angiotensin II is an octapeptide hormone and one of the active components of RAS. It plays a role in regulating water and electrolytes and plays a role by binding to its receptors
Renin (an endopeptidase) cleaves angiotensinogen into the decapeptide angiotensin (Ang I) I, which in turn is cleaved into the octapeptide Ang II by angiotensin-converting enzyme (ACE), a zinc metallopeptidase. Ang II is subsequently cleaved by ACE2, an ACE homologue, to Ang-1-7) (7). Ang II can bind to GPCRs G protein-coupled receptors including Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) and activate the mas receptor. AT1R activation not only leads to vasoconstriction, but also electrolyte and water retention by the kidney, but also inflammation, proliferation, and fibrosis (8).
On the other hand, activation of AT2R and mas receptor mediators have opposite effects including vasodilator, antiproliferative, antioxidant, anti-inflammatory and anti-fibrotic (8). Endogenous angiotensin 1-7 (a biologically active heptapeptide) is expressed in all different species at tissue levels comparable to angiotensin II (9).
This peptide is a prominent vasoactive component of RAS, which plays a role in neutralizing the physiological functions of angiotensin II due to its vasopressor, vasodilatory and antihypertensive effects (10). Due to several factors such as trauma, infection, severe poisoning, reaction to drugs or complications from surgeries (including kidney transplant), the kidney is damaged and malfunctions, and finally acute kidney injury (AKI) occurs. (11), which is associated with high mortality in hospitals and medical centers in developing countries. Every day, about 35% of patients in intensive care units get AKI (12). Imbalance in vasoactive substances, especially vasoconstrictor substances inside the kidney, even with a healthy tubular structure, is involved in the development of chronic hypoxia, especially in the early stages of kidney diseases before the development of histological changes in the tubulointerstitial tissue (2). Among the numerous vasoactive substances that are important in the pathophysiology of vessels is angiotensin II, which is the target of treatment due to its multiple actions in diseases (13).
Cisplatin (CP) is recognized as an anticancer drug for the treatment of solid tumors in clinical settings, but its main side effect is nephrotoxicity. CP may affect RAS components and it has been reported that AT1R antagonist has a protective role against CP-induced nephrotoxicity by increasing glomerular filtration rate (GFR) and renal blood flow (RBF) (14).
Inhibition of RAS vasopressor pathways in the kidney after CP in male rats has a protective role (15).
Therefore, to better understand and clarify the role of the renin-angiotensin system in cisplatin-induced nephrotoxicity, the present study will be conducted with the aim of investigating the role of the renin-angiotensin system in the model of cisplatin-induced nephrotoxicity.
Interference between the components of this system is one of the topics of interest to researchers. The RAS contains different receptors with different vascular responses. In addition to AT1, there are two other receptors. Angiotensin II receptor 2 (AT2) and angiotensin receptor (1-7) (Mas) in RAS are gender-dependent and the role of these receptors is more important in women than in men (1). The activity of the renin-angiotensin system (RAS) is important among vasoactive substances because it reduces renal perfusion and, as a result, hypoxia of the downstream tubulointerstitial tissue with the contraction of the efferent arteriole through the angiotensin type 1 receptor (AT1). Therefore, the role of RAS and its constituent factors or even factors affecting it in the process of renal ischemia-reperfusion has a special role. The AT1 receptor is one of the G protein-coupled receptors (GPCRs) that spans 7 times the width of the membrane. Its G protein is of the Gq type, but it lacks intrinsic tyrosine kinase activity (3). The binding of angiotensin II to this receptor activates phospholipase C (PLC) and causes the accumulation of inositol triphosphate (IP3) and diacylglycerol (DAG). By increasing the intracellular calcium concentration, IP3 causes vascular smooth muscle cell contraction and aldosterone secretion from the adrenal cortical part. DAG activates protein kinase C (PKC) and finally phosphorylates some proteins in this pathway, causing vascular contraction and cell growth. 3).
Kidney plays an important role in regulating arterial pressure and body fluid volume in connection with RAS (4). However, the role of the depressor of this system in regulating kidney function in physiological and disease conditions is not well known (5, 6). Angiotensin II type 2 receptor (AT2) and Mas receptor are part of RAS depressor arm (5, 6). Angiotensin II is an octapeptide hormone and one of the active components of RAS. It plays a role in regulating water and electrolytes and plays a role by binding to its receptors
Renin (an endopeptidase) cleaves angiotensinogen into the decapeptide angiotensin (Ang I) I, which in turn is cleaved into the octapeptide Ang II by angiotensin-converting enzyme (ACE), a zinc metallopeptidase. Ang II is subsequently cleaved by ACE2, an ACE homologue, to Ang-1-7) (7). Ang II can bind to GPCRs G protein-coupled receptors including Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) and activate the mas receptor. AT1R activation not only leads to vasoconstriction, but also electrolyte and water retention by the kidney, but also inflammation, proliferation, and fibrosis (8).
On the other hand, activation of AT2R and mas receptor mediators have opposite effects including vasodilator, antiproliferative, antioxidant, anti-inflammatory and anti-fibrotic (8). Endogenous angiotensin 1-7 (a biologically active heptapeptide) is expressed in all different species at tissue levels comparable to angiotensin II (9).
This peptide is a prominent vasoactive component of RAS, which plays a role in neutralizing the physiological functions of angiotensin II due to its vasopressor, vasodilatory and antihypertensive effects (10). Due to several factors such as trauma, infection, severe poisoning, reaction to drugs or complications from surgeries (including kidney transplant), the kidney is damaged and malfunctions, and finally acute kidney injury (AKI) occurs. (11), which is associated with high mortality in hospitals and medical centers in developing countries. Every day, about 35% of patients in intensive care units get AKI (12). Imbalance in vasoactive substances, especially vasoconstrictor substances inside the kidney, even with a healthy tubular structure, is involved in the development of chronic hypoxia, especially in the early stages of kidney diseases before the development of histological changes in the tubulointerstitial tissue (2). Among the numerous vasoactive substances that are important in the pathophysiology of vessels is angiotensin II, which is the target of treatment due to its multiple actions in diseases (13).
Cisplatin (CP) is recognized as an anticancer drug for the treatment of solid tumors in clinical settings, but its main side effect is nephrotoxicity. CP may affect RAS components and it has been reported that AT1R antagonist has a protective role against CP-induced nephrotoxicity by increasing glomerular filtration rate (GFR) and renal blood flow (RBF) (14).
Inhibition of RAS vasopressor pathways in the kidney after CP in male rats has a protective role (15).
Therefore, to better understand and clarify the role of the renin-angiotensin system in cisplatin-induced nephrotoxicity, the present study will be conducted with the aim of investigating the role of the renin-angiotensin system in the model of cisplatin-induced nephrotoxicity.
Received: 2023/08/27 | Accepted: 2023/11/11 | Published: 2024/08/31
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