Renin-angiotensin system as a potential target for new therapeutic approaches in Parkinson’s disease

Pérez-Lloret, Santiago; Otero‐Losada, Matilde; Toblli, Jorge Eduardo; Capani, Francisco

doi:10.1080/13543784.2017.1371133

Cited by 59 publications

(45 citation statements)

References 86 publications

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“…Conversely, longevity was associated with the suppression of this molecule (121). Indeed, ARBs and ACEi were found to be protective against both PD and AD, indicating that RAS may play a key role in neurodegeneration (122)(123)(124). Moreover, in 2017, the US Food and Drug Administration approved a synthetic form of human angiotensin II, Giapreza, for the treatment of septic shock.…”

Section: The Virus the Ras And The Dasmentioning

confidence: 99%

Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis

et al. 2020

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Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract).

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Section: The Virus the Ras And The Dasmentioning

confidence: 99%

Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis

et al. 2020

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“…The demonstration of local effects of both AT 2 R and Mas receptor signalling in the brain has led to the exploration of targeting the RAS for many neurological disorders, for example Parkinson's disease [ 216 ], depression [ 217 ], Alzheimer's Disease (AD) [ 218 ], cognitive impairment [ 219 ] or as reviewed here and elsewhere, the cerebrovascular disorder, stroke [ 220 ].…”

Section: Ras Receptor Signallingmentioning

confidence: 99%

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

McFall

Nicklin

Work

2020

Cellular Signalling

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Stroke is the 2nd leading cause of death worldwide and the leading cause of physical disability and cognitive issues. Although we have made progress in certain aspects of stroke treatment, the consequences remain substantial and new treatments are needed. Hypertension has long been recognised as a major risk factor for stroke, both haemorrhagic and ischaemic. The renin angiotensin system (RAS) plays a key role in blood pressure regulation and this, plus local expression and signalling of RAS in the brain, both support the potential for targeting this axis therapeutically in the setting of stroke. While historically, focus has been on suppressing classical RAS signalling through the angiotensin type 1 receptor (AT 1 R), the identification of a counter-regulatory axis of the RAS signalling via the angiotensin type 2 receptor (AT 2 R) and Mas receptor has renewed interest in targeting the RAS. This review describes RAS signalling in the brain and the potential of targeting the Mas receptor and AT 2 R in preclinical models of ischaemic stroke. The animal and experimental models, and the route and timing of intervention, are considered from a translational perspective.

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“…However, different laboratories have provided solid evidence of the relevant role of RAS in the central nervous system (CNS). Ang is an important regulator of motor control, and AT 1 R and AT 2 R have been suggested as targets to combat Parkinson's disease (PD) and related conditions such as levodopa (L-DOPA)-induced dyskinesias [38,45].…”

Section: Introductionmentioning

confidence: 99%

Angiotensin AT1 and AT2 receptor heteromer expression in the hemilesioned rat model of Parkinson’s disease that increases with levodopa-induced dyskinesia

Rivas‐Santisteban

Rodríguez‐Pérez

Muñoz

et al. 2020

J Neuroinflammation

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Background/aims: The renin-angiotensin system (RAS) is altered in Parkinson's disease (PD), a disease due to substantia nigra neurodegeneration and whose dopamine-replacement therapy, using the precursor levodopa, leads to dyskinesias as the main side effect. Angiotensin AT 1 and AT 2 receptors, mainly known for their role in regulating water homeostasis and blood pressure and able to form heterodimers (AT 1/2 Hets), are present in the central nervous system. We assessed the functionality and expression of AT 1/2 Hets in Parkinson disease (PD). Methods: Immunocytochemistry was used to analyze the colocalization between angiotensin receptors; bioluminescence resonance energy transfer was used to detect AT 1/2 Hets. Calcium and cAMP determination, MAPK activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify receptor expression in mouse primary cultures and in rat striatal sections. Results: We confirmed that AT 1 and AT 2 receptors form AT 1/2 Hets that are expressed in cells of the central nervous system. AT 1/2 Hets are novel functional units with particular signaling properties. Importantly, the coactivation of the two receptors in the heteromer reduces the signaling output of angiotensin. Remarkably, AT 1/2 Hets that are expressed in both striatal neurons and microglia make possible that candesartan, the antagonist of AT 1 , increases the effect of AT 2 receptor agonists. In addition, the level of striatal expression increased in the unilateral 6-OHdopamine lesioned rat PD model and was markedly higher in parkinsonian-like animals that did not become dyskinetic upon levodopa chronic administration if compared with expression in those that became dyskinetic. Conclusion: The results indicate that boosting the action of neuroprotective AT 2 receptors using an AT 1 receptor antagonist constitutes a promising therapeutic strategy in PD.

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Renin-angiotensin system as a potential target for new therapeutic approaches in Parkinson’s disease

Cited by 59 publications

References 86 publications

Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis

Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis

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

Angiotensin AT1 and AT2 receptor heteromer expression in the hemilesioned rat model of Parkinson’s disease that increases with levodopa-induced dyskinesia

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