NADPH oxidase-derived reactive oxygen species contribute to impaired cutaneous microvascular function in chronic kidney disease

DuPont, Jennifer J.; Ramick, Meghan G.; Farquhar, William B.; Townsend, Raymond R.; Edwards, David G.

doi:10.1152/ajprenal.00058.2014

Cited by 49 publications

(50 citation statements)

References 83 publications

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“…29, 30 In addition, apocynin perfusion through microdialysis probes has previously been found to blunt local angiotensin II-mediated vasoconstriction in the human cutaneous microvasculature, 31 and to restore local cutaneous vascular conductance in chronic kidney disease patients. 32 Thus, the findings in the present study that apocynin delivery via microdialysis augments local microvascular function are not without precedent. Conversely, apocynin incubation has been shown to have no effect on flow-induced dilation in coronary resistance arteries from cardiopulmonary bypass patients.…”

Section: Discussionmentioning

confidence: 54%

“…The marked inhibition of ROS by apocynin strongly suggests that apocynin does not have a pro-oxidant effect in this system. Despite the potential limitations of apocynin, it is by far the most commonly used Nox inhibitor available 31,32,35,37,40 , and at the concentrations employed by use in these studies, it is unrealistic to expect that any potential antioxidant effect of this compound could explain the effects observed here. A few subjects from each group dropped out of the exercise program prior to completion, thus data was not attained from these subjects for post-training measures.…”

Section: Discussionmentioning

confidence: 82%

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Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase

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Dubis

Yan

et al. 2016

ATVB

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Objective The objectives of this study were to determine the impact of in vivo reactive oxygen species (ROS) on microvascular endothelial function in obese human subjects and to determine the efficacy of an aerobic exercise intervention on alleviating obesity-associated dysfunctionality. Approach and Results Young, sedentary men and women were divided into lean (BMI 18–25; n=14), intermediate (BMI 28–32.5; n=13), and obese (BMI 33–40; n=15) groups. A novel microdialysis technique was utilized to detect elevated interstitial hydrogen peroxide (H2O2) and superoxide levels in the vastus lateralis of obese compared to both lean and intermediate subjects. Nutritive blood flow was monitored in the vastus lateralis via the microdialysis-ethanol technique. A decrement in acetylcholine-stimulated blood flow revealed impaired microvascular endothelial function in the obese subjects. Perfusion of apocynin, an NADPH oxidase (Nox) inhibitor, lowered (normalized) H2O2 and superoxide levels and reversed microvascular endothelial dysfunction in obese subjects. Following 8-weeks of exercise, H2O2 levels were decreased in the obese subjects and microvascular endothelial function in these subjects was restored to levels similar to lean subjects. Skeletal muscle protein expression of the Nox subunits p22phox, p47phox, and p67phox were increased in obese relative to lean subjects, where p22phox and p67phox expression was attenuated by exercise training in obese subjects. Conclusions This study implicates Nox as a source of excessive ROS production in skeletal muscle of obese individuals, and links excessive Nox derived ROS to microvascular endothelial dysfunction in obesity. Furthermore, aerobic exercise training proved to be an effective strategy for alleviating these maladies.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 82%

Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase

Favor

Dubis

Yan

et al. 2016

ATVB

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“…Indeed, impaired cutaneous microvascular function leading to attenuated vasodilation has been linked to attenuated NO bioavailability associated with elevated ROS, as decreasing O 2 − through the local administration of tempol, a SOD mimetic, restored cutaneous vasodilation in young smokers and patients with chronic kidney disease [133]. Moreover, inhibition of NADPH oxidase (apocynin) restored cutaneous vasodilation in the chronic kidney disease patients, suggesting an important role of this free radical producing enzymatic complex in the production of O 2 − [134]. Additionally, acute Vitamin C supplementation, alone or in combination with arginase, improved reflex cutaneous vasodilation during whole body heating in both older [135] and hypertensive [136] individuals.…”

Section: Free Radical Regulation Of Skin Blood Flowmentioning

confidence: 99%

Regulation of exercise blood flow: Role of free radicals

Trinity

Broxterman

Richardson

2016

Free Radical Biology and Medicine

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During exercise, oxygen and nutrient rich blood must be delivered to the active skeletal muscle, heart, skin, and brain through the complex and highly regulated integration of central and peripheral hemodynamic factors. Indeed, even minor alterations in blood flow to these organs have profound consequences on exercise capacity by modifying the development of fatigue. Therefore, the fine-tuning of blood flow is critical for optimal physical performance. At the level of the peripheral circulation, blood flow is regulated by a balance between the mechanisms responsible for vasodilation and vasoconstriction. Once thought of as toxic by-products of in vivo chemistry, free radicals are now recognized as important signaling molecules that exert potent vasoactive responses that are dependent upon the underlying balance between oxidation-reduction reactions or redox balance. Under normal healthy conditions with low levels of oxidative stress, free radicals promote vasodilation, which is attenuated with exogenous antioxidant administration. Conversely, with advancing age and disease where background oxidative stress is elevated, an exercise-induced increase in free radicals can further shift the redox balance to a pro-oxidant state, impairing vasodilation and attenuating blood flow. Under these conditions, exogenous antioxidants improve vasodilatory capacity and augment blood flow by restoring an “optimal” redox balance. Interestingly, while the active skeletal muscle, heart, skin, and brain all have unique functions during exercise, the mechanisms by which free radicals contribute to the regulation of blood flow is remarkably preserved across each of these varied target organs.

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“…To the contrary, we found that CKD was associated with a lower prevalence of VMS in this cohort. We speculate that pre-existing vascular disease among women with CKD including vascular calcification, arterial stiffness and impaired endothelial function 33,34 might interfere with vasodilation required to expel heat in VMS. Alternatively, the lower prevalence of VMS among women with CKD may be related to lower body temperature 35,36 in patients with CKD or alterations in the hypothalamic-pituitary axis.…”

Section: Discussionmentioning

confidence: 99%

Menopausal symptoms in women with chronic kidney disease

et al. 2015

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Objectives To determine if menopausal symptoms differed among women with versus without chronic kidney disease (CKD) and whether CKD modified associations of late vasomotor symptoms (VMS) with mortality and/or cardiovascular events. Methods Chronic kidney disease, defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 by the CKD-EPI equation, was determined in 17,891 postmenopausal women, aged 50–79 at baseline, in the multiethnic Women’s Health Initiative (WHI) cohort. Primary outcomes were presence, severity and timing/duration of VMS (self-reported hot flushes and night sweats) at baseline. We used polytomous logistic regression to test for associations among CKD and four VMS categories (none; early- present before menopause but not at enrollment; late- present only at enrollment; persistent- present before menopause and at enrollment) and determined whether CKD modified associations between late VMS and mortality or cardiovascular events, using Cox regression. Results Women with CKD (1017/17891; mean eGFR, 50.7mL/min/1.73m2) were more likely to have had menopause before age 45 (26% versus 23%, P=0.02), but were less likely to experience VMS (38% versus 46%, P<0.001) compared to women without CKD. Women with CKD were not more likely than women without CKD to experience late VMS. Late VMS (HR=1.16; 95% CI: 1.04, 1.29) and CKD (HR=1.74; 95% CI: 1.54, 1.97) were each independently associated with increased risk for mortality, but CKD did not modify the association of late VMS with mortality (Pinteraction=0.53), coronary heart disease (Pinteraction=0.12) or stroke (Pinteraction= 0.68). Conclusions Women with mild CKD experience earlier menopause and fewer VMS than women without CKD.

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NADPH oxidase-derived reactive oxygen species contribute to impaired cutaneous microvascular function in chronic kidney disease

Cited by 49 publications

References 83 publications

Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase

Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase

Regulation of exercise blood flow: Role of free radicals

Menopausal symptoms in women with chronic kidney disease

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