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Nadph-oxidase, rho-kinase and autophagy mediate the (Pro)renin-induced pro-inflammatory microglial response and enhancement of dopaminergic neuron death

Lopez-Lopez, Andrea ; Villar-Cheda, Begoña ; Quijano, Aloia ; Garrido-Gil, Pablo ; Garcia-Garrote, María LU orcid ; Díaz-Ruiz, Carmen ; Muñoz, Ana LU and Labandeira-Garcia, José L. (2021) In Antioxidants 10(9).
Abstract

Dysregulation of the tissue renin–angiotensin system (RAS) is involved in tissue oxidative and inflammatory responses. Among RAS components, renin, its precursor (pro)renin and its specific receptor (PRR) have been less investigated, particularly in the brain. We previously showed the presence of PRR in neurons and glial cells in the nigrostriatal system of rodents and primates, including humans. Now, we used rat and mouse models and cultures of BV2 and primary microglial cells to study the role of PRR in microglial pro-inflammatory responses. PRR was upregulated in the nigral region, particularly in microglia during the neuroinflammatory response. In the presence of the angiotensin type-1 receptor blocker losartan, to exclude... (More)

Dysregulation of the tissue renin–angiotensin system (RAS) is involved in tissue oxidative and inflammatory responses. Among RAS components, renin, its precursor (pro)renin and its specific receptor (PRR) have been less investigated, particularly in the brain. We previously showed the presence of PRR in neurons and glial cells in the nigrostriatal system of rodents and primates, including humans. Now, we used rat and mouse models and cultures of BV2 and primary microglial cells to study the role of PRR in microglial pro-inflammatory responses. PRR was upregulated in the nigral region, particularly in microglia during the neuroinflammatory response. In the presence of the angiotensin type-1 receptor blocker losartan, to exclude angiotensin-related effects, treatment of microglial cells with (pro)renin induces the expression of microglial pro-inflammatory markers, which is mediated by upregulation of NADPH-oxidase and Rho-kinase activities, downregulation of autophagy and upregulation of inflammasome activity. Conditioned medium from (pro)renintreated microglia increased dopaminergic cell death relative to medium from non-treated microglia. However, these effects were blocked by pre-treatment of microglia with the Rho-kinase inhibitor fasudil. Activation of microglial PRR enhances the microglial pro-inflammatory response and deleterious effects of microglia on dopaminergic cells, and microglial NADPH-oxidase, Rho-Kinase and autophagy are involved in this process.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Angiotensin, Autophagy, Dopamine, Microglia, Neurodegeneration, Neuroinflammation, Parkinson, Prorenin, Renin, ROCK
in
Antioxidants
volume
10
issue
9
article number
1340
publisher
MDPI AG
external identifiers
  • scopus:85113364448
ISSN
2076-3921
DOI
10.3390/antiox10091340
language
English
LU publication?
no
additional info
Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
id
575d9cfa-6f52-4877-b793-aa7342174425
date added to LUP
2025-01-24 12:04:30
date last changed
2025-04-04 14:12:59
@article{575d9cfa-6f52-4877-b793-aa7342174425,
  abstract     = {{<p>Dysregulation of the tissue renin–angiotensin system (RAS) is involved in tissue oxidative and inflammatory responses. Among RAS components, renin, its precursor (pro)renin and its specific receptor (PRR) have been less investigated, particularly in the brain. We previously showed the presence of PRR in neurons and glial cells in the nigrostriatal system of rodents and primates, including humans. Now, we used rat and mouse models and cultures of BV2 and primary microglial cells to study the role of PRR in microglial pro-inflammatory responses. PRR was upregulated in the nigral region, particularly in microglia during the neuroinflammatory response. In the presence of the angiotensin type-1 receptor blocker losartan, to exclude angiotensin-related effects, treatment of microglial cells with (pro)renin induces the expression of microglial pro-inflammatory markers, which is mediated by upregulation of NADPH-oxidase and Rho-kinase activities, downregulation of autophagy and upregulation of inflammasome activity. Conditioned medium from (pro)renintreated microglia increased dopaminergic cell death relative to medium from non-treated microglia. However, these effects were blocked by pre-treatment of microglia with the Rho-kinase inhibitor fasudil. Activation of microglial PRR enhances the microglial pro-inflammatory response and deleterious effects of microglia on dopaminergic cells, and microglial NADPH-oxidase, Rho-Kinase and autophagy are involved in this process.</p>}},
  author       = {{Lopez-Lopez, Andrea and Villar-Cheda, Begoña and Quijano, Aloia and Garrido-Gil, Pablo and Garcia-Garrote, María and Díaz-Ruiz, Carmen and Muñoz, Ana and Labandeira-Garcia, José L.}},
  issn         = {{2076-3921}},
  keywords     = {{Angiotensin; Autophagy; Dopamine; Microglia; Neurodegeneration; Neuroinflammation; Parkinson; Prorenin; Renin; ROCK}},
  language     = {{eng}},
  number       = {{9}},
  publisher    = {{MDPI AG}},
  series       = {{Antioxidants}},
  title        = {{Nadph-oxidase, rho-kinase and autophagy mediate the (Pro)renin-induced pro-inflammatory microglial response and enhancement of dopaminergic neuron death}},
  url          = {{http://dx.doi.org/10.3390/antiox10091340}},
  doi          = {{10.3390/antiox10091340}},
  volume       = {{10}},
  year         = {{2021}},
}