Sistema Renina-Angiotensina tisular/extracelular y sistema Renina-Angiotensina intracrino/intracelular en la Sustancia Negra. Posible papel en la enfermedad de Parkinson

El sistema Renina-Angiotensina (SRA) ha sido considerado clásicamente como un sistema hormonal o circulante encargado de la regulación de la presión arterial, pero actualmente se sabe que muchos tejidos tienen un SRA local, incluido el cerebro. Se ha demostrado la presencia de componentes del SRA en los ganglios basales, concretamente en el sistema nigroestriatal dopaminérgico, implicado en el desarrollo de la enfermedad de Parkinson (EP). Estudios recientes apoyan la existencia de un SRA intracrino o intracelular funcional que abre nuevas perspectivas para conocer su funcionamiento, concretamente, a nivel mitocondrial, presenta especial importancia puesto que se ha demostrado que la disfunción mitocondrial juega un papel fundamental en la degeneración de las neuronas dopaminérgicas y en la patogénesis de la EP. El envejecimiento es el mayor factor de riesgo para la EP. Además, se ha demostrado que la falta de estrógenos, que se produce durante la menopausia, aumenta el riesgo de sufrir esta enfermedad. Las alteraciones en la interacción de la dopamina y la angiotensina también juegan un papel importante en la vulnerabilidad dopaminérgica. De acuerdo con el papel fundamental que ejerce el SRA en la degeneración dopaminérgica, se ha encontrado una mayor actividad de este sistema en la sustancia negra de modelos animales con mayor vulnerabilidad dopaminérgica. La manipulación del SRA cerebral podría constituir una estrategia neuroprotectora eficaz contra la vulnerabilidad dopaminérgica, y por tanto, contra la progresión de la EP

The intracellular angiotensin system buffersdeleterious effects of the extracellular paracrine system

The‘classical’renin–angiotensin system (RAS) is a circulating system that controls blood pressure. Local/paracrine RAS,identified in a variety of tissues, including the brain, is involved in different functions and diseases, and RAS blockers arecommonly used in clinical practice. A third type of RAS (intracellular/intracrine RAS) has been observed in some types of cells,including neurons. However, its role is still unknown. The present results indicate that in brain cells the intracellular RAScounteracts the intracellular superoxide/H2O2and oxidative stress induced by the extracellular/paracrine angiotensin II acting onplasma membrane receptors. Activation of nuclear receptors by intracellular or internalized angiotensin triggers a number ofmechanisms that protect the cell, such as an increase in the levels of protective angiotensin type 2 receptors, intracellularangiotensin, PGC-1αand IGF-1/SIRT1. Interestingly, this protective mechanism is altered in isolated nuclei from brains of agedanimals. The present results indicate that at least in the brain, AT1 receptor blockers acting only on the extracellular or paracrineRAS may offer better protection of cellsWe thank Dr. Wei-Dong Le for providing the MES 23.5dopaminergic cell line, Dr. Manuel Serrano and Dr. Ruben Nogueiras for providing thetransgenic mice overexpressing SIRT1, and Dr. Daniel Henrion for providing the AT2KO mice. We thank Pilar Aldrey, Iria Novoa and Cristina Gianzo for their technicalassistance. This study was funded by the Spanish Ministry of Economy andCompetitiveness (BFU2015-70523), Spanish Ministry of Health (RD12/0019/0020,RD16/0011/0016 and CIBERNED), Galician Government (XUGA, GRC2014/002ED431G/05 and CIMUS accreditation 2016‐2019) and FEDER (Regional EuropeanDevelopment Fund)S

Renin angiotensin system and gender differences in dopaminergic degeneration

Background: There are sex differences in dopaminergic degeneration. Men are approximately two times as likely as premenopausal women of the same age to develop Parkinson’s disease (PD). It has been shown that the local renin angiotensin system (RAS) plays a prominent role in sex differences in the development of chronic renal and cardiovascular diseases, and there is a local RAS in the substantia nigra and dopaminergic cell loss is enhanced by angiotensin via type 1 (AT1) receptors. Results: In the present study, we observed that intrastriatal injection of 6-hydroxydopamine induced a marked loss of dopaminergic neurons in the substantia nigra of male rats, which was significantly higher than the loss induced in ovariectomized female rats given estrogen implants (i.e. rats with estrogen). However, the loss of dopaminergic neurons was significantly lower in male rats treated with the AT1 antagonist candesartan, and similar to that observed in female rats with estrogen. The involvement of the RAS in gender differences in dopaminergic degeneration was confirmed with AT1a-null mice lesioned with the dopaminergic neurotoxin MPTP. Significantly higher expression of AT1 receptors, angiotensin converting enzyme activity, and NADPH-oxidase complex activity, and much lower levels of AT2 receptors were observed in male rats than in female rats with estrogen. Conclusions: The results suggest that brain RAS plays a major role in the increased risk of developing PD in men, and that manipulation of brain RAS may be an efficient approach for neuroprotective treatment of PD in men, without the feminizing effects of estrogen.Funding: Spanish Ministry of Science and Innovation, Spanish Ministry of Health (RD06/0010/0013 and CIBERNED), Galician Government (XUGA) and FEDERS

Autoantibodies against ACE2 and angiotensin type-1 receptors increase severity of COVID-19

The renin-angiotensin system (RAS) plays a major role in COVID-19. Severity of several inflammation-related diseases has been associated with autoantibodies against RAS, particularly agonistic autoantibodies for angiotensin type-1 receptors (AA-AT1) and autoantibodies against ACE2 (AA-ACE2). Disease severity of COVID-19 patients was defined as mild, moderate or severe following the WHO Clinical Progression Scale and determined at medical discharge. Serum AA-AT1 and AA-ACE2 were measured in COVID-19 patients (n = 119) and non-infected controls (n = 23) using specific solid-phase, sandwich enzyme-linked immunosorbent assays. Serum LIGHT (TNFSF14; tumor necrosis factor ligand superfamily member 14) levels were measured with the corresponding assay kit. At diagnosis, AA-AT1 and AA-ACE2 levels were significantly higher in the COVID-19 group relative to controls, and we observed significant association between disease outcome and serum AA-AT1 and AA-ACE2 levels. Mild disease patients had significantly lower levels of AA-AT1 (p < 0.01) and AA-ACE2 (p < 0.001) than moderate and severe patients. No significant differences were detected between males and females. The increase in autoantibodies was not related to comorbidities potentially affecting COVID-19 severity. There was significant positive correlation between serum levels of AA-AT1 and LIGHT (TNFSF14; rPearson = 0.70, p < 0.001). Both AA-AT1 (by agonistic stimulation of AT1 receptors) and AA-ACE2 (by reducing conversion of Angiotensin II into Angiotensin 1-7) may lead to increase in AT1 receptor activity, enhance proinflammatory responses and severity of COVID-19 outcome. Patients with high levels of autoantibodies require more cautious control after diagnosis. Additionally, the results encourage further studies on the possible protective treatment with AT1 receptor blockers in COVID-19Axencia Galega de Innovación (IN845D 2020/20). Spanish Ministry of Economy and Competitiveness (RTI2018-098830-B-I00). Spanish Ministry of Health (PI17/00828, RD16/0011/0016 and CIBERNED). Galician Government (XUGA, ED431C 2018/10, ED431G/05). FEDER (Regional European Development Fund)S

AT1 receptor autoantibodies mediate effects of metabolic syndrome on dopaminergic vulnerability

The metabolic syndrome has been associated to chronic peripheral inflammation and related with neuroinflammation and neurodegeneration, including Parkinson’s disease. However, the responsible mechanisms are unclear. Previous studies have involved the brain renin-angiotensin system in progression of Parkinson’s disease and the angiotensin receptor type 1 (AT1) has been recently revealed as a major marker of dopaminergic vulnerability in humans. Dysregulation of tissue renin-angiotensin system is a key common mechanism for all major components of metabolic syndrome. Circulating AT1 agonistic autoantibodies have been observed in several inflammation-related peripheral processes, and activation of AT1 receptors of endothelial cells, dopaminergic neurons and glial cells have been observed to disrupt endothelial blood -brain barrier and induce neurodegeneration, respectively. Using a rat model, we observed that metabolic syndrome induces overactivity of nigral pro-inflammatory renin-angiotensin system axis, leading to increase in oxidative stress and neuroinflammation and enhancing dopaminergic neurodegeneration, which was inhibited by treatment with AT1 receptor blockers (ARBs)S