Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial calcium overload

Hong, Quan; Qi, Ka; Feng, Zhe; Huang, Zhiyong; Cui, Shaoyuan; Wang, Liyuan; Fu, Bo; Ding, Rui; Yang, Jurong; Chen, Xiangmei; Wu, Di

doi:10.1016/j.ceca.2012.01.003

Cited by 93 publications

(73 citation statements)

References 60 publications

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“…Because our previous study demonstrated that uric acid could induce ROS generation that subsequently caused endothelial dysfunction [9], we focused on the oxidative stress process in this study. Based on our gene-pathway and GO-protein networks (supporting information), we noticed that catalase (CAT) was related to oxidative stress and was upregulated approximately 6.4-fold more in the SGR treatment group than in the HUA group.…”

Section: Resultsmentioning

confidence: 99%

“…However, the mechanism of its protective effects on renal function under hyperuricemic conditions is not known. It has been demonstrated that the production of reactive oxygen species (ROS) increased significantly under hyperuricemic conditions [8], and our previous studies [9,10] and other research [11,12,13,14] have confirmed that high concentrations of uric acid could cause endothelial dysfunction by generating reactive oxidative species (ROS), which induce calcium overload and inflammation. It has also been reported that high concentrations of uric acid could induce renal failure by damaging endothelial cells [15], but the underlying mechanism remains unclear.…”

Section: Introductionmentioning

confidence: 94%

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Smilacis Glabrae RhizomaReduces Oxidative Stress Caused by Hyperuricemia via Upregulation of Catalase

Hong

Yu²,

Mei³

et al. 2014

Cell Physiol Biochem

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Background/Aims: Reports have suggested that the traditional Chinese medicine Smilacis Glabrae Rhizoma attenuates hyperuricemia, but its mechanism is unclear. Our previous study demonstrated that uric acid could induce the generation of reactive oxygen species(ROS), which subsequently cause endothelial dysfunction. Therefore, we focused on the oxidative stress process. In this study, we would use LC-MS and bioinformatic analysis to investigate the underlying mechanism. Methods: We utilized LC-MS to reveal the differential protein expression in the kidneys of rats in the hyperuricemia group and the Smilacis Glabrae Rhizoma treatment group and then subjected the differentially expressed proteins to bioinformatic analysis. We also determined the serum ROS level of the two groups. According the above results, we built our hypothesis and performed in vitro experiments to validate this hypothesis. Results: We found that catalase was upregulated in the group treated with Smilacis Glabrae Rhizoma, and the level of reactive oxygen species was higher in the hyperuricemia group. Thus, we speculated that Smilacis Glabrae Rhizoma could alleviate oxidative stress by upregulating catalase. In vitro experiments, we found that high concentrations of uric acid reduced catalase expression in endothelial cells, which was alleviated by Smilacis Glabrae Rhizoma and resulted in a reduction of reactive oxygen species. Knockdown of catalase led to an increase in reactive oxygen species. Conclusion: We demonstrated that Smilacis Glabrae Rhizoma could alleviate the oxidative stress caused by hyperuricemia by upregulating catalase expression. This finding could represent a new application for Smilacis Glabrae Rhizoma in the treatment of hyperuricemia.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Smilacis Glabrae RhizomaReduces Oxidative Stress Caused by Hyperuricemia via Upregulation of Catalase

Hong

Yu²,

Mei³

et al. 2014

Cell Physiol Biochem

Self Cite

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“…For example, a high concentration of serum uric acid may reduce the release of nitric oxide (NO) 20,21) or increase the level of mitochondrial O 2 , which is associated with mitochondrial calcium overload 22) , ultimately leading to endothelial cell dysfunction. In addition, uric acid acts as a pro-inflammatory cytokine and plays an important role in the proliferation of vascular smooth muscle cells 23) and inflammatory reactions in adipose tissue 24) , which in turn results in an increased thickness of the carotid arteries.…”

Section: Discussionmentioning

confidence: 99%

Impact of the Serum Uric Acid Level on Subclinical Atherosclerosis in Middle-aged and Elderly Chinese

Chen

Sun

et al. 2015

JAT

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Aim:The carotid intima-media thickness (CIMT) is now validated as a sensitive marker of atherosclerosis and is directly associated with an increased risk of cardiovascular disease. Considering that the independent association between the serum uric acid level and CIMT remains controversial due to the complex interrelationship with other known cardiovascular risk factors, further studies are needed. The aim of the present study is to explore the association between the serum uric acid level and CIMT in a general Chinese population and determine whether the association differs according to varied metabolic status. Methods: The present study was cross-sectional in design. A total of 10,281 community-based participants 40 years of age or older from Shanghai, China were included in the current analysis. All participants underwent a detailed questionnaire interview, anthropometric measurements and ultrasonography to assess the CIMT. Blood and urine samples were collected for the biochemical measurements. Results: The serum uric acid levels were positively associated with obesity-and diabetes-related parameters and the CIMT. In a logistic regression model controlling for potential confounders, compared with the participants in the first quartile of the uric acid level, those in the fourth quartile had a higher odds of an elevated CIMT in both men (odds ratio [OR] 1.37; 95% confidence interval [CI] 1.07-1.75) and women (OR 1.48; 95% CI 1.12-1.94). The subgroup analyses revealed that an association between an elevated CIMT and the serum uric acid level persisted regardless of diuretic use and the hypertension, diabetes mellitus and chronic kidney disease status. However, the association disappeared in the patients who consumed alcohol and in premenopausal women. Conclusions: The serum uric acid level is positively associated with an elevated CIMT in middleaged and elderly Chinese subjects, independent of known risk determinants of cardiovascular disease. J Atheroscler Thromb, 2015; 22: 823-832.

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“…Given the underlying antioxidant-prooxidant urate redox shuttle, the antioxidant uric acid at the normal plasma concentration becomes a prooxidant induced by multiple injurious stimuli (55). Hyperuricemia induces endothelial dysfunction by increasing mitochondrial superoxide generation triggered by mitochondrial calcium overload (62), which may be caused by calpain 1 cleavage of Na ϩ /Ca 2ϩ exchangers. Calpains are Ca 2ϩ -activated non-lysosomal cysteine proteases, and the subunit members, such as calpain 1, 2, and 10, induce necrosis and apoptosis of endothelial cells in the kidney, thereby increasing the plasma membrane permeability (129).…”

Section: Acquired Mitochondrial Dysfunction In Kidney Diseasementioning

confidence: 99%

Mitochondrial dysfunction in the pathophysiology of renal diseases

Che

Yuan

Huang

et al. 2014

American Journal of Physiology-Renal Physiology

328

272

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Mitochondrial dysfunction has gained recognition as a contributing factor in many diseases. The kidney is a kind of organ with high energy demand, rich in mitochondria. As such, mitochondrial dysfunction in the kidney plays a critical role in the pathogenesis of kidney diseases. Despite the recognized importance mitochondria play in the pathogenesis of the diseases, there is limited understanding of various aspects of mitochondrial biology. This review examines the physiology and pathophysiology of mitochondria. It begins by discussing mitochondrial structure, mitochondrial DNA, mitochondrial reactive oxygen species production, mitochondrial dynamics, and mitophagy, before turning to inherited mitochondrial cytopathies in kidneys (inherited or sporadic mitochondrial DNA or nuclear DNA mutations in genes that affect mitochondrial function). Glomerular diseases, tubular defects, and other renal diseases are then discussed. Next, acquired mitochondrial dysfunction in kidney diseases is discussed, emphasizing the role of mitochondrial dysfunction in the pathogenesis of chronic kidney disease and acute kidney injury, as their prevalence is increasing. Finally, it summarizes the possible beneficial effects of mitochondrial-targeted therapeutic agents for treatment of mitochondrial dysfunction-mediated kidney injury-genetic therapies, antioxidants, thiazolidinediones, sirtuins, and resveratrol-as mitochondrial-based drugs may offer potential treatments for renal diseases.

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Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial calcium overload

Cited by 93 publications

References 60 publications

Smilacis Glabrae RhizomaReduces Oxidative Stress Caused by Hyperuricemia via Upregulation of Catalase

Smilacis Glabrae RhizomaReduces Oxidative Stress Caused by Hyperuricemia via Upregulation of Catalase

Impact of the Serum Uric Acid Level on Subclinical Atherosclerosis in Middle-aged and Elderly Chinese

Mitochondrial dysfunction in the pathophysiology of renal diseases

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