Genetic Silencing of Nox2 and Nox4 Reveals Differential Roles of These NADPH Oxidase Homologues in the Vasopressor and Dipsogenic Effects of Brain Angiotensin II

Peterson, Jeffrey R.; Burmeister, Melissa A.; Tian, Xin; Zhang, Yi; Guruju, Mallikarjuna R.; Stupinski, John A.; Sharma, Ram V.; Davisson, Robin L.

doi:10.1161/hypertensionaha.109.140087

Cited by 92 publications

(105 citation statements)

References 51 publications

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…Importantly, and relevant to the present findings, Ang II's actions on PVN neurons play a key role in regulating sympathetic nervous system activity in relation to cardiovascular function, particularly hypertension (8,48). Some mechanisms for these actions include elevations of inflammation and oxidant stress locally within the brain (8,33,63,74), which have also been implicated in the central regulation of energy balance (18,34). In fact, the effects of icv Ang II on energy balance are strikingly similar to those of the cytokine TNF␣ (3,18).…”

Section: Discussionsupporting

confidence: 55%

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 55%

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

View full text Add to dashboard Cite

show abstract

“…The pressor response to central Ang II is predominently mediated by AT 1 receptor stimulation, and drinking response and release of vasopressin are mediated by both AT 1 and AT 2 receptors stimulation. 9 Peterson et al 30 showed that both nicotinamide adenine dinucleotide phosphate oxidases, NOX2 and NOX4, in the SFO contribute to Intracerebroventricular infusion of Ang II at 2.5 ng/min increases BP maximally by 20 mm Hg within the first 1 to 2 days, and BP remains at this level during the next 2 weeks. Intracerebroventricular infusion of FAD286 or eplerenone does not affect the initial increase in BP, but from day 3, reverses the elevated BP toward control values.…”

Section: Discussionmentioning

confidence: 99%

Role of Brain Corticosterone and Aldosterone in Central Angiotensin II–Induced Hypertension

et al. 2013

View full text Add to dashboard Cite

Abstract-Circulating angiotensin II (Ang II) activates a central aldosterone-mineralocorticoid receptor neuromodulatory pathway, which mediates most of the Ang II-induced hypertension. This study examined whether specific central infusion of Ang II also activates this central aldosterone-mineralocorticoid receptor pathway. Intracerebroventricular infusion of Ang II at 1.0, 2.5, and 12.5 ng/min for 2 weeks caused dose-related increases in water intake, Ang II concentration in the cerebrospinal fluid, and blood pressure. Intracerebroventricular Ang II, at 2.5 and 12.5 ng/min, increased hypothalamic aldosterone and corticosterone, as well as plasma aldosterone and corticosterone without affecting plasma Ang II levels. Intracerebroventricular infusion of the aldosterone synthase inhibitor FAD286-but not the mineralocorticoid receptor blocker eplerenone-inhibited by ≈60% the Ang II-induced increase in hypothalamic aldosterone. Both blockers attenuated by ≈50% the increase in plasma aldosterone and corticosterone with only minimal effects on hypothalamic corticosterone. By telemetry, intracerebroventricular infusion of Ang II maximally increased blood pressure within the first day with no further increase over the next 2 weeks.

show abstract

“…After screening each of the shRNAs in TIB-73 cells (an immortalized mouse hepatocyte cell line) for knockdown of G6PD protein, we selected viruses 4 and 5 (named Ad.shG6PD4 and Ad.shG6PD5) for further in vivo experiments. For knock-down of NOX4, we used a previously characterized recombinant adenoviral vector expressing shRNA against mouse NOX4 (Ad.shNOX4) (44). We used an adenovirus (Ad.shGFP) that expresses shRNA against GFP as a control (45).…”

Section: Methodsmentioning

confidence: 99%

Control of Hepatic Nuclear Superoxide Production by Glucose 6-Phosphate Dehydrogenase and NADPH Oxidase-4

Spencer

Yan

Boudreau³

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Redox-regulated signal transduction is coordinated by spatially controlled production of reactive oxygen species within subcellular compartments. The nucleus has long been known to produce superoxide (O 2 . ); however, the mechanisms that control this function remain largely unknown. We have characterized molecular features of a nuclear superoxide-producing system in the mouse liver. Using electron paramagnetic resonance, we investigated whether several NADPH oxidases (NOX1, 2, and 4) and known activators of NOX (Rac1, Rac2, p22 phox , and p47 phox ) contribute to nuclear O 2 . production in isolated hepatic nuclei.Our findings demonstrate that NOX4 most significantly contributes to hepatic nuclear O 2 . production that utilizes NADPH as an electron donor. Although NOX4 protein immunolocalized to both nuclear membranes and intranuclear inclusions, fluorescent detection of NADPH-dependent nuclear O 2 . predominantly localized to the perinuclear space. Interestingly, NADP ؉ and G6P also induced nuclear O 2 . production, suggesting that intranuclear glucose-6-phosphate dehydrogenase (G6PD) can control NOX4 activity through nuclear NADPH production. Using G6PD mutant mice and G6PD shRNA, we confirmed that reductions in nuclear G6PD enzyme decrease the ability of hepatic nuclei to generate O 2 . in response to NADP ؉ and G6P.NOX4 and G6PD protein were also observed in overlapping microdomains within the nucleus. These findings provide new insights on the metabolic pathways for substrate regulation of nuclear O 2 . production by NOX4.Reactive oxygen species (ROS) 2 such as superoxide (O 2 . ) and H 2 O 2 play important roles in cellular oxidative stress as well as in the regulation of cellular signal transduction in the healthy state. Understanding the regulatory pathways that control cellular ROS at specific sites in the cell is vital to determining their function in cell signaling (1). Important for the regulation of redox signaling is the controlled production of ROS at specific intracellular sites such as mitochondria and endosomes. ROS production and transport at these locations are tightly regulated and linked to effector redox signals (2-6). Another, much less studied, site of ROS production is the nucleus. Despite the fact that NADPH-dependent O 2 . production by the nucleus was discovered over three decades ago (7-10), the regulation and function of nuclear O 2 . remain largely uncharacterized.Over the years, several enzymes including cytochrome P450 and many others have been suggested as candidate sources of nuclear O 2 . . More recently, endothelial nuclei disrupted by sonication (11), and endothelial nuclear protein extracts (12) have both been shown to produce ROS that is, at least in part, NOX4-dependent. NOX4 has been localized in nuclei of vascular smooth muscle cells, but its subnuclear localization (such as within specific nuclear membranes) remains unclear (13). Nuclear NOX4 has also been implicated in DNA damage resulting from both hemangioendothelioma formation (14) and hepatitis C infection (15...

show abstract

Genetic Silencing of Nox2 and Nox4 Reveals Differential Roles of These NADPH Oxidase Homologues in the Vasopressor and Dipsogenic Effects of Brain Angiotensin II

Cited by 92 publications

References 51 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

Role of Brain Corticosterone and Aldosterone in Central Angiotensin II–Induced Hypertension

Control of Hepatic Nuclear Superoxide Production by Glucose 6-Phosphate Dehydrogenase and NADPH Oxidase-4

Contact Info

Product

Resources

About