Uric Acid-Induced Endothelial Dysfunction Is Associated with Mitochondrial Alterations and Decreased Intracellular ATP Concentrations

Sánchez‐Lozada, Laura G.; Lanaspa, Miguel A.; Cristóbal-García, Magdalena; García-Arroyo, Fernando E.; Soto, Virgilia; Cruz-Robles, David; Nakagawa, Takahiko; Yu, Min; Kang, Duk Hee; Johnson, Richard J.

doi:10.1159/000345509

Cited by 273 publications

(224 citation statements)

References 48 publications

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“…High levels of UA were previously found to induce mitochondrial dysfunction, which may lead to excess ROS generation. This suggested that mitochondrial uncoupling decreases the synthesis of ATP via oxidative phosphorylation (Sánchez-Lozada et al, 2012). Therefore, we hypothesized that the decrease in ATP content in the hepatocyte mitochondria was correlated with mitochondrial uncoupling promoted by UA-induced ROS.…”

Section: Discussionmentioning

confidence: 95%

Effect of uric acid on mitochondrial function and oxidative stress in hepatocytes

et al. 2016

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ABSTRACT. Here, we investigated the effect of uric acid (UA) on hepatocyte mitochondria. Hepatocytes cultured in vitro were treated with varying concentrations of UA. The change in apoptotic activity was detected by flow cytometry. The DNA damage index 8-hydroxy-deoxyguanosine (8-OHdG) and mitochondrial function indices succinate dehydrogenase (SDH), cytochrome C oxidase (CCO), and adenosine triphosphate (ATP) were detected by enzyme assays. Reactive oxygen species (ROS) accumulation was confirmed by a dichloro-dihydrofluorescein diacetate assay. We observed an increase in apoptotic activity, ROS accumulation, and 8-OHdG activity in hepatocytes treated with UA for extended periods, indicating DNA damage; specifically, we observed a significant increase in these activities 48, 72, and 96 h after UA addition, compared to those observed at 24 h (P < 0.05). Cells treated with 30 mg/dL UA for 96 h showed a peak in apoptotic activity. We also observed a significant decrease in ATP, SDH, and CCO activities with the increase in uric acid concentration over time. Cells treated with 30 mg/dL UA for 96 h showed the highest ATP levels, while SDH and CCO activities at 48, 72, and 96 h post-UA treatment were significantly lower than those at 24 h (P < 0.01). Moreover, cells treated with 30 mg/dL UA showed a 0.02 ± 0.02 and 0.15 ± 0.01 mmol/ mg/min decrease in SDH and CCO levels after 72 h. Therefore, we concluded that high concentrations of UA may induce oxidative stress in hepatocyte mitochondria, increasing ROS production and ultimately resulting in mitochondrial damage.

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Section: Discussionmentioning

confidence: 95%

Effect of uric acid on mitochondrial function and oxidative stress in hepatocytes

et al. 2016

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“…18 Uric acid is known to stimulate MCP-1/CCL2 and oxidative stress in vascular smooth muscle cells 20,21 and endothelial cells. 22,23 Experimentally, uric acid has been shown to activate the renin angiotensin system, induce microvascular disease, alter renal autoregulation, and increase glomerular hydrostatic pressure. 18,24 Fructose can also increase the expression of intercellular adhesion molecule-1 in vascular endothelial cells throughout the kidney.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

Lanaspa

Ishimoto

Cicerchi

et al. 2014

Journal of the American Society of Nephrology

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141

146

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Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase-deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.

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“…It has been reported that UA-induced endothelial dysfunction is associated with decreased intracellular ATP concentrations and mitochondrial alterations (24). Therefore, the present study evaluated whether LA treatment affects mitochondrial mass and function in the process of hyperuricemia.…”

Section: La Rescues Vascular Endothelial Cell Mitochondrial Mass Andmentioning

confidence: 93%

Protective role of α-lipoic acid in hyperuricemia-induced endothelial dysfunction

Zou

Wang

Liu

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The aim of the current study was to determine the effects of α-lipoic acid (LA) on hyperuricemia and endothelial dysfunction, and to uncover the underlying mechanism of its action. A hyperuricemic rat model was established by administration of uric acid (UA) and the rats were orally fed with 2 g/kg/day LA or phosphate-buffered saline. Primary rat aortic endothelial cells were subsequently isolated, and a cell viability assay, apoptosis assay, enzyme nitric oxide synthase (eNOS) activity assay and mitochondrial function assay were all performed. For the in vitro study, human umbilical vein endothelial cells were used and western blotting was performed to assess Akt signaling activity. The results of the current study indicated that LA inhibited apoptosis, enhanced eNOS activity and production of nitric oxide (NO), and rescued mitochondrial mass and function in uric acid (UA)-treated endothelial cells. LA activated Akt signaling and inhibition of Akt signaling abolished the effects of LA on cell viability, NO production, ROS production and ATP levels in UA-treated endothelial cells. Therefore, the current study demonstrated that LA attenuated oxidant stress and inhibited apoptosis in UA-treated endothelial cells by activating Akt signaling. The results indicate that LA may serve as a therapeutic approach to treat hyperuricemia-induced endothelial dysfunction.

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Uric Acid-Induced Endothelial Dysfunction Is Associated with Mitochondrial Alterations and Decreased Intracellular ATP Concentrations

Cited by 273 publications

References 48 publications

Effect of uric acid on mitochondrial function and oxidative stress in hepatocytes

Effect of uric acid on mitochondrial function and oxidative stress in hepatocytes

Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

Protective role of α-lipoic acid in hyperuricemia-induced endothelial dysfunction

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