Abstract
Brain insulin signaling is accounted for the development of a variety of neuropsychiatric disorders, such as anxiety and depression, whereas both inflammation and the activated renin-angiotensin system (RAS) are two major contributors to insulin resistance. Intriguingly, inflammation and RAS can activate each other, forming a positive feedback loop that would result in exacerbated unwanted tissue damage. To further examine the interrelationship among insulin signaling, neuroinflammation and RAS in the brain, the effect of repeated lipopolysaccharide (LPS) exposure and co-treatment with the angiotensin II (Ang II) receptor type 1 (AT1) blocker, candesartan (Cand), on anxiety and depression-like behaviors, RAS, neuroinflammation and insulin signaling was explored. Our results demonstrated that prolonged LPS challenge successfully induced the rats into anxiety and depression-like state, accompanied with significant neural apoptosis and neuroinflammation. LPS also activated RAS as evidenced by the enhanced angiotensin converting enzyme (ACE) expression, Ang II generation and AT1 expression. However, blocking the activated RAS with Cand co-treatment conferred neurobehavioral protective properties. The AT1 blocker markedly ameliorated the microglial activation, the enhanced gene expression of the proinflammatory cytokines and the overactivated NF-κB signaling. In addition, Cand also mitigated the LPS-induced disturbance of insulin signaling with the normalized phosphorylation of serine 307 and tyrosine 896 of insulin receptor substrate-1 (IRS-1). Collectively, the present study, for the first time, provided the direct evidence indicating that the inflammatory condition may interact with RAS to impede brain insulin pathway, resulting in neurobehavioral damage, and inhibiting RAS seems to be a promising strategy to block the cross-talk and cut off the vicious cycle between RAS and immune system.
Highlights
Renin-angiotensin system (RAS) is originally acknowledged for its role in the regulation of blood pressure, but it is generally accepted that brain has its intrinsic RAS with the major components, including angiotensin converting enzyme (ACE) and angiotensin II (Ang II) receptor type 1 (AT1), widely distributed in the central nervous system (Haspula and Clark, 2018; Uijl et al, 2018)
LPS induced the animals to a depression-like state with increased immobility time in Forced Swim Test (FST) (Figure 1E) and longer latency to feed in Novelty-Suppressed Feeding Test (NSFT) (Figure 1F)
In line with our previous research, repeated administration of LPS induced anxiety and depression-like behaviors, as well as neuroinflammation, in rats, which resembles the clinical profile of depression that depressive patients are prone to under chronic subclinical inflammatory state (Dang et al, 2017)
Summary
Renin-angiotensin system (RAS) is originally acknowledged for its role in the regulation of blood pressure, but it is generally accepted that brain has its intrinsic RAS with the major components, including angiotensin converting enzyme (ACE) and angiotensin II (Ang II) receptor type 1 (AT1), widely distributed in the central nervous system (Haspula and Clark, 2018; Uijl et al, 2018). The brain RAS actively participates in various neurological functions, including cognition, memory, emotion and stress response, and RAS over-activation has been identified in several neuropsychiatric disorders, including Alzheimer’s disease, epilepsy and depression (Yagi et al, 2013; Gebre et al, 2018). These disorders are frequently characterized with neurodegeneration, inflammation and brain insulin resistance. In this context, the interrelationship between RAS and these neuropathological progresses is attracting increasing attention, since Ang II is recognized as a pleiotropic factor locally metabolized in the brain (Saavedra, 2017). Despite the consensus that neuroinflammation and insulin resistance are two hallmarks of neuropathy, in both of which RAS plays an essential role, the evidence concerning intricate interrelationship among RAS, immune system and insulin signaling is limited and controversial, especially in the brain
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