Angiotensin Receptor Type 1 Blockade in Astroglia Decreases Hypoxia-Induced Cell Damage and TNF Alpha Release

Danielyan, Lusine; Lourhmati, Ali; Verleysdonk, Stephan; Kabisch, Daniela; Proksch, Barbara; Thiess, Ulrike; Umbreen, Sumaira; Schmidt, Boris; Gleiter, Christoph H.

doi:10.1007/s11064-007-9337-6

Cited by 22 publications

(19 citation statements)

References 46 publications

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“…In fact, the effects of icv Ang II on energy balance are strikingly similar to those of the cytokine TNF␣ (3,18). This, coupled with the fact that TNF␣'s secretion is also regulated by Ang II (15), implies that TNF␣ may be involved in some of Ang II's effects on energy balance.…”

Section: Discussionmentioning

confidence: 88%

Central angiotensin II has catabolic action at white and brown adipose tissue

Kloet

Krause

Scott

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Considerable evidence implicates the renin-angiotensin system (RAS) in the regulation of energy balance. To evaluate the role of the RAS in the central nervous system regulation of energy balance, we used osmotic minipumps to chronically administer angiotensin II (Ang II; icv; 0.7 ng/min for 24 days) to adult male Long-Evans rats, resulting in reduced food intake, body weight gain, and adiposity. The decrease in body weight and adiposity occurred relative to both ad libitum-and pair-fed controls, implying that reduced food intake in and of itself does not underlie all of these effects. Consistent with this, rats administered Ang II had increased whole body heat production and oxygen consumption. Additionally, chronic icv Ang II increased uncoupling protein-1 and ␤ 3-adrenergic receptor expression in brown adipose tissue and ␤3-adrenergic receptor expression in white adipose tissue, which is suggestive of enhanced sympathetic activation and thermogenesis. Chronic icv Ang II also increased hypothalamic agouti-related peptide and decreased hypothalamic proopiomelanocortin expression, consistent with a state of energy deficit. Moreover, chronic icv Ang II increased the anorectic corticotrophin-and thyroid-releasing hormones within the hypothalamus. These results suggest that Ang II acts in the brain to promote negative energy balance and that contributing mechanisms include an alteration in the hypothalamic circuits regulating energy balance, a decrease in food intake, an increase in energy expenditure, and an increase in sympathetic activation of brown and white adipose tissue. food intake; obesity; renin-angiotensin system MILLIONS OF PEOPLE SUFFER FROM OBESITY and the concomitant susceptibility to cardiovascular disease and type 2 diabetes, and emerging evidence has implicated the renin-angiotensin system (RAS) as contributing to these disorders; one consequence is that the RAS has emerged as a novel target for the treatment of these comorbidities (5,6,30,68,70,83). The RAS is best known as an endocrine system important in the regulation of cardiovascular function and hydromineral balance; however, recent evidence suggests that RAS also plays a substantial role in the regulation of energy and glucose homeostasis (5,6,30,68,70,83). Most physiological actions of the RAS are exerted by angiotensin II (Ang II), a peptide that is synthesized from angiotensinogen (AGT) via a series of proteolytic cleavage events. Drugs that reduce Ang II synthesis [angiotensinconverting enzyme (ACE) inhibitors] or action [angiotensin type 1 receptor blockers (ARBs)] have been used to treat hypertension for decades, and more recently, clinical and preclinical studies have explored the utility of these pharmacological agents to promote insulin sensitivity (1, 57). Interestingly, we and others have identified a potential novel utility of these pharmacological agents as therapeutics for obesity using animal models (4,16,21,76,84,85).Although interference with systemic RAS activity consistently decreases body weight and fat in rodent studie...

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Section: Discussionmentioning

confidence: 88%

Central angiotensin II has catabolic action at white and brown adipose tissue

Kloet

Krause

Scott

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…Astrocytes were previously thought to be nonexcitable support cells of the brain, but recent findings refute this notion (46). Furthermore, despite the fact that AT 1 expression is very weak in normal states, it is increased in hypoxic conditions (7). Moreover, insertion of an AT 1 R transgene into the RVLM using adenoviral vectors results in the expression of AT 1 R in the glia as well as increased blood pressure, probably due to increased sympathetic activity (2).…”

Section: Discussionmentioning

confidence: 99%

“…Although AT 1 R are weakly expressed in astrocytes under basal conditions (28, 35), they have important roles in abnormal conditions, such as experimental autoimmune encephalomyelitis, and in the regulation of leukocyte infiltration into the central nervous system in response to a neurodegenerative stimulus as well as hypoxia (7,11,26). AT 1 R in glia cells in the RVLM are thought to be involved in the regulation of blood pressure associated with sympathetic activation (2).…”

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confidence: 99%

Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

Isegawa

Hirooka

Katsuki

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Isegawa K, Hirooka Y, Katsuki M, Kishi T, Sunagawa K. Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure. Am J Physiol Heart Circ Physiol 307: H1448 -H1455, 2014. First published September 12, 2014 doi:10.1152/ajpheart.00462.2014.-Enhanced central sympathetic outflow worsens left ventricular (LV) remodeling and prognosis in heart failure after myocardial infarction (MI). Previous studies suggested that activation of brain angiotensin II type 1 receptors (AT 1R) in the brain stem leads to sympathoexcitation due to neuronal AT 1R upregulation. Recent studies, however, revealed the importance of astrocytes for modulating neuronal activity, but whether changes in astrocytes influence central sympathetic outflow in heart failure is unknown. In the normal state, AT1R are only weakly expressed in astrocytes. We hypothesized that AT1R in astrocytes are upregulated in heart failure and modulate the activity of adjacent neurons, leading to enhanced sympathetic outflow. In the present study, by targeting deletion of astrocyte-specific AT 1R, we investigated whether AT1R in astrocytes have a key role in enhancing central sympathetic outflow, and thereby influencing LV remodeling process and the prognosis of MI-induced heart failure. Using the Cre-LoxP system, we generated glial fibrillary acidic protein (GFAP)-specific AT1R knockout (GFAP/ AT 1RKO) mice. Urinary norepinephrine excretion for 24 h, as an indicator of sympathoexcitation, was significantly lower in GFAP/ AT 1RKO-MI mice than in control-MI mice. LV size and heart weight after MI were significantly smaller in GFAP/AT 1RKO mice than in control mice. Prognosis was significantly improved in GFAP/ AT 1RKO-MI mice compared with control-MI mice. Our findings indicated that AT 1R expression was upregulated in brain stem astrocytes in MI-induced heart failure, which worsened LV remodeling and prognosis via sympathoexcitation. Thus, in addition to neuronal AT 1R, AT1R in astrocytes appear to have a key role in enhancing central sympathetic outflow in heart failure.astrocyte; angiotensin II type 1 receptor; sympathetic nervous system; heart failure ENHANCED central sympathetic outflow is a cardinal manifestation of heart failure, which influences the left ventricular (LV) remodeling process and eventually worsens prognosis (10, 45). Activation of brain angiotensin II type 1 receptors (AT 1 R) enhances sympathetic outflow in experimental heart failure (12, 13, 30). Furthermore, activation of AT 1 R has a major role in the production of reactive oxygen species (ROS) in the brain stem and hypothalamus (5, 17). For example, ROS blockade in the central nervous system by intracerebroventricular injection of superoxide dismutase or tempol prevents sympathoexcitation after myocardial infarction (MI) (19). In particular, AT 1 Rinduced ROS production in the rostral ventrolateral medulla (RVLM) contributes to enhance the sympathetic outflow in heart failure (12, 13). Previou...

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“…Our findings are consistent with the previous observations that Ang II via AT 1 receptor stimulation could induce Aldo release in astrocytes to participate in various pathophysiologic processes, such as hypoxia-associated neurodegeneration. 33 As Aldo also has a direct role in oxidative stress, 21 it seems that oxidative stress may also be related to the neuron-damaging effect of Aldo. More detailed examination of the toxic factors that directly cause SGN damage and the signaling pathways involved in Ang II-and Aldoinduced SGN damage with the involvement of astrocytes could contribute to further elucidation of the pathogenesis of CNS disorders.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II and aldosterone-induced neuronal damage in neurons through an astrocyte-dependent mechanism

et al. 2011

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The contribution of the renin-angiotensin-aldosterone system (RAAS) to central nervous system (CNS) disorders is not yet fully understood. RAAS has been shown to be involved in the proliferation of astrocytes, which have a role in neuronal damage contributing to neurodegenerative diseases. However, the direct relationship between RAAS and neuronal damage is still unclear. We therefore examined the effect of angiotensin (Ang) II and aldosterone (Aldo) on damage to spinal ganglion neurons (SGNs) by regulating astrocytes. Ang II stimulation significantly increased DNA damage in SGNs in a time-dependent manner. This increase in DNA damage was further enhanced when SGNs were co-cultured with astrocytes. On the other hand, no significant increase was observed in SGNs co-cultured with astrocytes without Ang II stimulation. Moreover, the addition of conditioned medium from Ang II-treated astrocytes exacerbated SGN DNA damage. An Ang II type 1 receptor blocker, valsartan, inhibited Ang II-stimulated DNA damage but not DNA damage induced by conditioned medium prepared from astrocyte cultures. In contrast, an Aldo antagonist, eplerenone, significantly inhibited DNA damage induced by the culture medium from Ang II-treated astrocytes. Ang II-stimulated Aldo secretion in the conditioned medium from astrocytes. Furthermore, the administration of Aldo alone also enhanced DNA damage in SGNs. Finally, flow cytometric analysis showed that Ang II or Aldo treatment markedly increased the percentage of dead SGNs. In conclusion, Ang II-and Aldo-induced neuronal damage in SGNs through astrocytes regulation. Blocking Ang II and Aldo to target astrocytes might be useful for the treatment of CNS disorders.

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Angiotensin Receptor Type 1 Blockade in Astroglia Decreases Hypoxia-Induced Cell Damage and TNF Alpha Release

Cited by 22 publications

References 46 publications

Central angiotensin II has catabolic action at white and brown adipose tissue

Central angiotensin II has catabolic action at white and brown adipose tissue

Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

Angiotensin II and aldosterone-induced neuronal damage in neurons through an astrocyte-dependent mechanism

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