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 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)renin-treated 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.
Highlights
The renin–angiotensin system (RAS) is present in most tissues, including the brain, and dysregulation of tissue RAS is involved in the inflammatory response related to different diseases and aging-related pro-inflammatory processes [1,2,3,4]
The RAS is organized into two axes that counteract each other to establish a correct balance in physiological conditions: a pro-inflammatory and pro-oxidative arm mainly represented by angiotensin II (AngII) and angiotensin type 1 (AT1) receptors, and an anti-inflammatory and anti-oxidative arm formed by AngII/AT2 receptors together with Ang1-7/Mas receptors (MasR) [7,8]
Rats were injected in the medial forebrain bundle with the dopaminergic neurotoxin 6-OHDA, and the nigral region was analyzed for PRR expression one week after the injection or four weeks after the lesion [25,26]; four weeks after the lesion, a group of rats was injected with L-DOPA to induce dyskinetic behavior, which is accompanied by an increase in pro-inflammatory markers in the nigra [27,28,29], and nigral PRR expression was analyzed
Summary
The renin–angiotensin system (RAS) is present in most tissues, including the brain, and dysregulation of tissue RAS is involved in the inflammatory response related to different diseases and aging-related pro-inflammatory processes [1,2,3,4]. ACE2 plays a central role in the balance by transforming components of the pro-inflammatory arm Among RAS components, renin and its precursor (pro)renin (PR) together with their specific receptor (PRR) have been less investigated, despite they play a major role in RAS function. AngII-dependent actions, as it is classically known that renin hydrolyzes the RAS precursor protein angiotensinogen into AngI ( transformed into AngII by ACE); binding of renin to PRR increases the catalytic activity of renin by about 4–5 times, and binding of pro-renin induces catalytic activity similar to that of renin [9,10,11,12]. AngII-independent actions by triggering a PRR-derived intracellular signaling cascade, which effects are usually considered to be pro-inflammatory and included as a component of the pro-oxidative pro-inflammatory arm [9,10,11,12]. The PRR intracellular effects are complex and the intracellular pathways involved in these effects are unclear
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