The counter regulatory axis of the renin angiotensin system in the brain and ischaemic stroke: Insight from preclinical stroke studies and therapeutic potential

McFall, Aisling; Nicklin, Stuart A.; Work, Lorraine M.

doi:10.1016/j.cellsig.2020.109809

Cited by 17 publications

(20 citation statements)

References 275 publications

(363 reference statements)

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“… Proposed angiotensin II and H 2 O 2 -induced NO elevation in podocytes. Angiotensin-II metabolites may activate production of NO in cells through AT2R or Mas receptors [ 70 , 71 ]. Activation of this GPCR is followed by PI3-K/Akt-dependent NOS phosphorylation and subsequent NO production [ 71 , 72 ].…”

Section: Figurementioning

confidence: 99%

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Nitric-Oxide-Mediated Signaling in Podocyte Pathophysiology

et al. 2022

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Nitric oxide (NO) is a potent signaling molecule involved in many physiological and pathophysiological processes in the kidney. NO plays a complex role in glomerular ultrafiltration, vasodilation, and inflammation. Changes in NO bioavailability in pathophysiological conditions such as hypertension or diabetes may lead to podocyte damage, proteinuria, and rapid development of chronic kidney disease (CKD). Despite the extensive data highlighting essential functions of NO in health and pathology, related signaling in glomerular cells, particularly podocytes, is understudied. Several reports indicate that NO bioavailability in glomerular cells is decreased during the development of renal pathology, while restoring NO level can be beneficial for glomerular function. At the same time, the compromised activity of nitric oxide synthase (NOS) may provoke the formation of peroxynitrite and has been linked to autoimmune diseases such as systemic lupus erythematosus. It is known that the changes in the distribution of NO sources due to shifts in NOS subunits expression or modifications of NADPH oxidases activity may be linked to or promote the development of pathology. However, there is a lack of information about the detailed mechanisms describing the production and release of NO in the glomerular cells. The interaction of NO and other reactive oxygen species in podocytes and how NO-calcium crosstalk regulates glomerular cells’ function is still largely unknown. Here, we discuss recent reports describing signaling, synthesis, and known pathophysiological mechanisms mediated by the changes in NO homeostasis in the podocyte. The understanding and further investigation of these essential mechanisms in glomerular cells will facilitate the design of novel strategies to prevent or manage health conditions that cause glomerular and kidney damage.

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Section: Figurementioning

confidence: 99%

“…Angiotensin-II metabolites may activate production of NO in cells through AT2R or Mas receptors [ 70 , 71 ]. Activation of this GPCR is followed by PI3-K/Akt-dependent NOS phosphorylation and subsequent NO production [ 71 , 72 ]. Angiotensin II binds to its receptors and activates NADPH oxidase, which in turn increases ROS generation.…”

Section: Figurementioning

confidence: 99%

Nitric-Oxide-Mediated Signaling in Podocyte Pathophysiology

et al. 2022

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“…In ischemic stroke, therapeutic manipulation of brain RAS has been investigated to control blood pressure ( 54 ) and blockade of the classical RAS with ACE inhibitors and selective AT 1 R inhibitors (ARBs) has proven more effective than beta-blockers for secondary prevention of stroke ( 55 ). The relationship between RAS and stroke has been recently summarized ( 56 , 57 ). Briefly, AT 1 R-deficient mice have a larger penumbra area and a smaller area of energy failure than wild-type littermates after middle cerebral artery occlusion (MCAO) ( 58 ).…”

Section: Introductionmentioning

confidence: 99%

Angiotensin-(1–7) as a Potential Therapeutic Strategy for Delayed Cerebral Ischemia in Subarachnoid Hemorrhage

et al. 2022

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Aneurysmal subarachnoid hemorrhage (SAH) is a substantial cause of mortality and morbidity worldwide. Moreover, survivors after the initial bleeding are often subject to secondary brain injuries and delayed cerebral ischemia, further increasing the risk of a poor outcome. In recent years, the renin–angiotensin system (RAS) has been proposed as a target pathway for therapeutic interventions after brain injury. The RAS is a complex system of biochemical reactions critical for several systemic functions, namely, inflammation, vascular tone, endothelial activation, water balance, fibrosis, and apoptosis. The RAS system is classically divided into a pro-inflammatory axis, mediated by angiotensin (Ang)-II and its specific receptor AT1R, and a counterbalancing system, presented in humans as Ang-(1–7) and its receptor, MasR. Experimental data suggest that upregulation of the Ang-(1–7)/MasR axis might be neuroprotective in numerous pathological conditions, namely, ischemic stroke, cognitive disorders, Parkinson’s disease, and depression. In the presence of SAH, Ang-(1–7)/MasR neuroprotective and modulating properties could help reduce brain damage by acting on neuroinflammation, and through direct vascular and anti-thrombotic effects. Here we review the role of RAS in brain ischemia, with specific focus on SAH and the therapeutic potential of Ang-(1–7).

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“…The “counter-regulatory” axis involves the type 2 AngII receptor (AT2) and the MAS receptor, through AngII (AT2) and Ang1-7 (AT2, MAS). These receptors promote vasodilation, natriuresis, anti-inflammation, anti-fibrosis, and anti-proliferative responses that counterbalance AT1 effects [ 3 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Evolutionary information helps understand distinctive features of the angiotensin II receptors AT1 and AT2 in amniota

et al. 2022

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In vertebrates, the octopeptide angiotensin II (AngII) is an important in vivo regulator of the cardiovascular system. It acts mainly through two G protein-coupled receptors, AT1 and AT2. To better understand distinctive features of these receptors, we carried out a phylogenetic analysis that revealed a mirror evolution of AT1 and AT2, each one split into two clades, separating fish from terrestrial receptors. It also revealed that hallmark mutations occurred at, or near, the sodium binding site in both AT1 and AT2. Electrostatics computations and molecular dynamics simulations support maintained sodium binding to human AT1 with slow ingress from the extracellular side and an electrostatic component of the binding free energy around -3kT, to be compared to around -2kT for human AT2 and the δ opioid receptor. Comparison of the sodium binding modes in wild type and mutated AT1 and AT2 from humans and eels indicates that the allosteric control by sodium in both AT1 and AT2 evolved during the transition from fish to amniota. The unusual S7.46N mutation in AT1 is mirrored by a L3.36M mutation in AT2. In the presence of sodium, the N7.46 pattern in amniota AT1 stabilizes the inward orientation of N3.35 in the apo receptor, which should contribute to efficient N3.35 driven biased signaling. The M3.36 pattern in amniota AT2 favours the outward orientation of N3.35 and the receptor promiscuity. Both mutations have physiological consequences for the regulation of the renin-angiotensin system.

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The counter regulatory axis of the renin angiotensin system in the brain and ischaemic stroke: Insight from preclinical stroke studies and therapeutic potential

Cited by 17 publications

References 275 publications

Nitric-Oxide-Mediated Signaling in Podocyte Pathophysiology

Nitric-Oxide-Mediated Signaling in Podocyte Pathophysiology

Angiotensin-(1–7) as a Potential Therapeutic Strategy for Delayed Cerebral Ischemia in Subarachnoid Hemorrhage

Evolutionary information helps understand distinctive features of the angiotensin II receptors AT1 and AT2 in amniota

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