Endothelial Nox4 NADPH Oxidase Enhances Vasodilatation and Reduces Blood Pressure In Vivo

Ray, Robin; Murdoch, Colin E.; Wang, Minshu; Santos, Célio X.C.; Zhang, Min; Alom-Ruiz, Sara P.; Anilkumar, Narayana; Ouattara, Alexandre; Cave, Alison C.; Walker, Simon; Grieve, David; Charles, Rebecca L.; Eaton, Philip; Brewer, Alison C.; Shah, Ajay M.

doi:10.1161/atvbaha.110.219238

Cited by 288 publications

(247 citation statements)

References 37 publications

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“…Deletion of either Nox4 or -2 in STZ-induced diabetes is not beneficial and may even be deleterious in the case of Nox4, supporting studies showing that Nox4 may play a protective role in chronic kidney injury and endothelial dysfunction. [43][44][45][46] However, the role of Nox4 remains controversial in the diabetic setting, because short-term pharmacological Nox4 inhibition reduces renal ROS generation, glomerular hypertrophy, and fibronectin expression. 42 Unlike other Nox family members, nothing is known regarding the function of Nox5 in animal models of disease, owing mainly to its absence from the mouse and rat genome.…”

Section: Discussionmentioning

confidence: 99%

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Holterman¹,

Thibodeau²,

Towaij³

et al. 2014

Journal of the American Society of Nephrology

113

122

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NADPH oxidase (Nox) enzymes are a significant source of reactive oxygen species, which contribute to glomerular podocyte dysfunction. Although studies have implicated Nox1, -2, and -4 in several glomerulopathies, including diabetic nephropathy, little is known regarding the role of Nox5 in this context. We examined Nox5 expression and regulation in kidney biopsies from diabetic patients, cultured human podocytes, and a novel mouse model. Nox5 expression increased in human diabetic glomeruli compared with nondiabetic glomeruli. Stimulation with angiotensin II upregulated Nox5 expression in human podocyte cultures and increased reactive oxygen species generation. siRNA-mediated Nox5 knockdown inhibited angiotensin II-stimulated production of reactive oxygen species and altered podocyte cytoskeletal dynamics, resulting in an Rac-mediated motile phenotype. Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5 pod+ ). Nox5 pod+ mice exhibited early onset albuminuria, podocyte foot process effacement, and elevated systolic BP. Subjecting Nox5 pod+ mice to streptozotocin-induced diabetes further exacerbated these changes. Our data show that renal Nox5 is upregulated in human diabetic nephropathy and may alter filtration barrier function and systolic BP through the production of reactive oxygen species. These findings provide the first evidence that podocyte Nox5 has an important role in impaired renal function and hypertension. Albuminuria is a clinical marker of kidney dysfunction that arises in most glomerulopathies and is associated with poor prognoses for ESRD, hypertension, and cardiovascular mortality. Changes to the podocyte (e.g., foot process effacement, hypertrophy, detachment, and loss) underlie the development and progression of albuminuria and thereby highlight the critical role for these cells in upholding the glomerular filtration barrier. 1,2 Therefore, identifying factors that induce podocyte injury and loss is essential to understanding the mechanisms of filtration barrier dysfunction. Of the many factors implicated in podocyte dysfunction, excessive production of reactive oxygen species (ROS; oxidative stress) may be particularly important. [3][4][5][6] Although sources of ROS are numerous, the NADPH oxidase (Nox) family of enzymes yields significant superoxide production in the

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Section: Discussionmentioning

confidence: 99%

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Holterman¹,

Thibodeau²,

Towaij³

et al. 2014

Journal of the American Society of Nephrology

113

122

View full text Add to dashboard Cite

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“…Recent studies demonstrated that Nox4 may actually have protective effects, possibly through Nox4-derived H 2 O 2 , which may act as a vasodilator in some vascular beds (164,238). This could explain why mice with targeted endothelial Nox4 overexpression have lower blood pressure and improved endothelium-dependent vasodilation versus wild-type controls (164).…”

Section: Nox4mentioning

confidence: 99%

“…Redox Signal. 20,[164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182] …”

Section: Introductionunclassified

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

Montezano

Touyz²

2014

Antioxidants & Redox Signaling

232

177

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Significance: Reactive oxygen species (ROS) are signaling molecules that are important in physiological processes, including host defense, aging, and cellular homeostasis. Increased ROS bioavailability and altered redox signaling (oxidative stress) have been implicated in the onset and/or progression of chronic diseases, including hypertension. Recent Advances: Although oxidative stress may not be the only cause of hypertension, it amplifies blood pressure elevation in the presence of other pro-hypertensive factors, such as salt loading, activation of the renin-angiotensin-aldosterone system, and sympathetic hyperactivity, at least in experimental models. A major source for ROS in the cardiovascular-renal system is a family of nicotinamide adenine dinucleotide phosphate oxidases (Noxs), including the prototypic Nox2-based Nox, and Nox family members: Nox1, Nox4, and Nox5. Critical Issues: Although extensive experimental data support a role for increased ROS levels and altered redox signaling in the pathogenesis of hypertension, the role in clinical hypertension is unclear, as a direct causative role of ROS in blood pressure elevation has yet to be demonstrated in humans. Nevertheless, what is becoming increasingly evident is that abnormal ROS regulation and aberrant signaling through redoxsensitive pathways are important in the pathophysiological processes which is associated with vascular injury and target-organ damage in hypertension. Future Directions: There is a paucity of clinical information related to the mechanisms of oxidative stress and blood pressure elevation, and a few assays accurately measure ROS directly in patients. Such further ROS research is needed in humans and in the development of adequately validated analytical methods to accurately assess oxidative stress in the clinic. Antioxid. Redox Signal. 20,[164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182]

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“…In disease states, it is well established that elevated expression and activity of NADPH oxidase isoforms in the vasculature, together with the resulting increased ROS production, contribute to the initiation and maintenance of the atherosclerotic process. However, it should be noted that recent studies have unveiled a distinct, potentially beneficial role for the Rac1-independent Nox4 isoform in the vascular wall, by enhancing vasodilation in a H 2 O 2 -mediated way (91), underlying the fact that controlled ROS production in specific cellular compartments may be beneficial for vascular homeostasis, as they serve as signaling molecules that mediate multiple biological processes.…”

Section: Fig 4 Effects Of Statins On Enos In Ecsmentioning

confidence: 99%

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

Margaritis

Channon

Antoniades

2014

Antioxidants & Redox Signaling

116

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Significance: Endothelial dysfunction and the imbalance between nitric oxide (NO) and reactive oxygen species production in the vascular endothelium are important early steps in atherogenesis, a major socioeconomic health problem. Statins have well-established roles in primary and secondary prevention of cardiovascular disease (CVD), due to both their lipid-lowering capacity and their pleiotropic properties. It is therefore important to understand the mechanisms by which statins can modify endothelial function and affect atherogenesis. Recent Advances: In the last decade, the concept of statin pleiotropy has been reinforced by a large number of cell culture, animal, and translational studies. Statins have been shown to suppress the activity of pro-oxidant enzymes (such as NADPH oxidase) and pro-inflammatory transcriptional pathways in the endothelium. At the same time, they enhance endothelial NO synthase expression and activity while they also improve its enzymatic coupling. This leads to increased NO bioavailability and improved endothelial function. Critical Issues: Despite significant recent advances, the exact mechanisms of statin pleitropy are still only partially understood. The vast majority of the published literature relies on animal studies, while the actual mechanistic studies in humans are limited. Future Directions: The success of statins as endothelium redox-modifying agents with a direct impact on clinical outcome highlights the importance of the endothelium as a therapeutic target in CVD. Better understanding of the mechanisms that underlie endothelial dysfunction could lead to the design of novel therapeutic strategies that target the vascular endothelium for the prevention and treatment of CVD. Antioxid. Redox Signal. 20, 1198Signal. 20, -1215

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Endothelial Nox4 NADPH Oxidase Enhances Vasodilatation and Reduces Blood Pressure In Vivo

Cited by 288 publications

References 37 publications

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

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