Reciprocal regulation between sirtuin-1 and angiotensin-II in the substantia nigra: implications for aging and neurodegeneration

Abstract

Local angiotensin II (AII) and sirtuin 1 (SIRT1) play a major role in the modulation of neuroinflammation, oxidative stress and aging-related dopaminergic vulnerability to damage. However, it is not known whether the modulation is related to reciprocal regulation between SIRT1 and AII. In the present study, a single intraventricular injection of AII increased nigral SIRT1 levels in young adult rats. Although AII activity is known to be increased in aged rats, levels of SIRT1 were significantly lower than in young controls. Treatment with the SIRT1-activating compound resveratrol increased nigral SIRT1 levels in aged rats. Levels of SIRT1 were significantly higher in aged wild type mice than in AII type-1 receptor (AT1) deficient mice. In cell culture studies, treatment with AII also induced a transitory increase in levels of SIRT1 in the MES 23.5 dopaminergic neuron and the N9 microglial cell lines. In aged rats, treatment with resveratrol induced a significant decrease in the expression of AT1 receptors and markers of NADPH-oxidase activation (p47 phox ).In aged transgenic mice over-expressing SIRT1, levels of AT1 and p47 phox were lower than in aged wild type controls. In vitro, the inhibitory effects of resveratrol on AII/ AT1/NADPH-oxidase activity were confirmed in primary mesencephalic cultures, the N9 microglial cell line, and the dopaminergic neuron cell line MES 23.5, and they were blocked by the SIRT1 specific inhibitor EX527. The present findings show that SIRT1 and the axis AII/AT1/NADPH-oxidase regulate each other. This is impaired in aged animals and may be mitigated with sirtuin-activating compounds.

Crosstalk between insulin-like growth factor-1 and angiotensin-II in dopaminergic neurons and glial cells: role in neuroinflammation and aging

“…Inhibitory effects on the neuroinflammatory response [ 39 ], improvement in mitochondrial function [ 40 ], inhibition of OS and Sirtuin-1 activation [ 41 , 42 ] have been suggested as possible mechanisms. Interestingly, the brain RAS has been shown to be involved in neuroinflammation [ 38 , 43 ], mitochondrial function [ 23 , 24 ] and Sirtuin-1 activity [ 44 ] in PD models. The results of the present study show a reciprocal regulation between IGF-1 and RAS: IGF-1 inhibited RAS activity in neurons and glial cells (i.e.…”

“…Four or sixteen hours after the AII injection the rats were killed and processed for western blotting (WB). The effective doses of AII and survival periods were determined on the basis of our previous findings [ 44 , 53 ]. As RAS activity in the nigral region is known to be higher in aged rats than in young rats (i.e.…”

How efficient is resveratrol as an antioxidant of the Mediterranean diet, towards alterations during the aging process?

“…On the other hand, enhanced the expression of SIRT1 through the activation of AMP-activated protein kinase (AMPK). SIRT1 mitigates LPS-mediated proinflammatory cytokines release in microglia [72,73]. Moreover, RSV diminished NADPH oxidase-mediated generation of reactive oxygen species and such effect has been suggested to be dependent on SIRT1 [73,74].…”

“…SIRT1 mitigates LPS-mediated proinflammatory cytokines release in microglia [72,73]. Moreover, RSV diminished NADPH oxidase-mediated generation of reactive oxygen species and such effect has been suggested to be dependent on SIRT1 [73,74]. Benefit of RSV is also illustrated by the induction of anti-inflammatory cytokine IL-10 through dependent up-regulation of suppressor of cytokine signalling-3 (SOCS3), which requires the Janus kinase/signal transducers and activators of transcription (JAK-STAT) signalling pathway [75].…”

Brain Renin–Angiotensin System Blockade Attenuates Methamphetamine-Induced Hyperlocomotion and Neurotoxicity

“…Ang II type 1 and 2 receptors (AT 1 -R and AT 2 -R) are expressed in the mesolimbic dopaminergic neurons, and Ang II facilitates dopamine release in the striatum through interaction with AT 1 -R both in vitro and in vivo [16]. Moreover, AT 1 -R is highly expressed in DA-rich brain areas [17,18]. AT 1 -R antagonist increases dopamine D1 receptor (D1R) but decreases D3R expression [19,20].…”