Abstract
The tissue renin–angiotensin system (RAS) has been shown to be involved in prooxidative and proinflammatory changes observed in aging and aging-related diseases such as dopaminergic degeneration in Parkinson’s disease (PD). We studied the activation of the NLRP3 inflammasome in the substantia nigra with aging and early stages of dopaminergic degeneration in PD models and, particularly, if the brain RAS, via its prooxidative proinflammatory angiotensin II (AngII) type 1 (AT1) receptors, mediates the inflammasome activation. Nigras from aged rats and mice and 6-hydroxydopamine PD models showed upregulation in transcription of inflammasome-related components (NLRP3, pro-IL1β and pro-IL18) and IL1β and IL18 protein levels, which was inhibited by the AT1 receptor antagonist candesartan. The role of the AngII/AT1 axis in inflammasome activation was further confirmed in rats intraventricularly injected with AngII, and in primary mesencephalic cultures treated with 6-hydroxydopamine, which showed inflammasome activation that was blocked by candesartan. Observations in the nigra of young and aged AT1 and AT2 knockout mice confirmed the major role of AT1 receptors in nigral inflammasome activation. In conclusion, the inflammasome is upregulated by aging and dopaminergic degeneration in the substantia nigra, possibly related with a decrease in dopamine levels, and it is mediated by the AngII/AT1 axis.
Highlights
Introduction iationsA proinflammatory state is observed in most tissues during aging, and facilitates development of aging-related chronic diseases [1,2]
In the substantia nigra of aged rats, we observed a significant increase in the expression of mRNA of major NLRP3 inflammasome components (NLRP3, pro-IL1β and pro-IL18)
We observed a significant increase in levels of IL1β and IL18 in the substantia nigra of aged rats relative to the substantia nigra of young rats
Summary
A proinflammatory state is observed in most tissues during aging (inflammaging), and facilitates development of aging-related chronic diseases [1,2]. In the brain, aging-related neuroinflammation promotes progression of major neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease [3]. The renin–angiotensin system (RAS), local or tissue RAS, has been related to prooxidative and proinflammatory changes observed in aging and aging-related diseases in several peripheral tissues, cardiovascular and renal tissues [4]. The brain has a local RAS, and dysregulation of brain RAS has been observed in aged brains [5,6] and animal models of neurodegenerative diseases, including PD [7,8]. The tissue RAS physiological function involves the correct balance between two arms, which counteract each other: a prooxidative and proinflammatory axis mainly constituted.
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