Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells

Zhang, Yongneng; Yamamoto, Tetsuya; Hisatome, Ichiro; Li, Youfeng; Cheng, Wei; Sun, Ning; Cai, Bin; Huang, Tianliang; Yang, Zhu; Li, Zhi; Jing, Xubin; Zhou, Rui; Cheng, Juei‐Tang

doi:10.1016/j.mce.2013.04.027

Cited by 108 publications

(100 citation statements)

References 31 publications

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“…UA has been demonstrated to trigger the upregulation of ROS in several cell types. ROS are able to regulate or induce multiple cellular processes, including epithelial-mesenchymal transition (19), growth (20), cell differentiation (21) and apoptosis (7)(8)(9)13). The present study indicated that UA induced apoptosis in renal tubular cells by inducing ROS, which may cause cell loss and tubular dysfunction during the progression of CKD.…”

Section: Discussionmentioning

confidence: 99%

Nox4 has a crucial role in uric acid-induced oxidative stress and apoptosis in renal tubular cells

Sheng

Liu

et al. 2016

Molecular Medicine Reports

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Abstract. The purpose of the present study was to evaluate the effects of uric acid in promoting tubular cell apoptosis and verify the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4)-induced oxidative stress in this process. HK-2 cells were used as a human proximal tubular cell model and co-cultured with various concentrations of uric acid with or without pre-treatment with the Nox4 inhibitor diphenylene iodonium (DPI). The apoptotic rate and the amount of reactive oxygen species (ROS) were examined by flow cytometry. Furthermore, levels of Nox4, phosphorylated (p)-P38, p-extracellular signal-regulated kinase (ERK), B-cell lymphoma 2 (Bcl-2) and Bcl-2-extra large (Bax) were detected by western blot analysis. The results showed that treatment with uric acid decreased HK-2 cell viability and promoted apoptosis in a dose-dependent manner. This was paralleled with an upregulation of Nox4 as well as ROS overproduction, which activated the phosphorylation of P38/ERK and caused an imbalance of Bax/Bcl-2 in HK-2 cells. Of note, inhibition of Nox4 with DPI prevented uric acid-induced cell injury by suppressing ROS generation and P38/ERK activation. In conclusion, it was demonstrated that elevated uric acid promoted ROS-induced tubular cell apoptosis by upregulating Nox4 expression. The present study therefore provided possible mechanisms and a potential therapeutic target of uric acid-induced chronic kidney disease.

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Section: Discussionmentioning

confidence: 99%

Nox4 has a crucial role in uric acid-induced oxidative stress and apoptosis in renal tubular cells

Sheng

Liu

et al. 2016

Molecular Medicine Reports

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“…This process involved the ERK1/2 pathway as part of the downstream signaling of urate-derived ROS, which was consistent with the findings of other studies. 38,39) In agreement with the involvement of oxidative stress, treatment with an antioxidant abolished urate-induced enhancement of the Kv1.5 protein channel. The possible mechanisms underlying uric acid-induced enhancement of Kv1.5 protein expression are shown in Figure 2.…”

Section: Intracellular Accumulation Of Uric Acid Causes Pathological mentioning

confidence: 53%

“…36) Several reports have indicated that hyperuricemia induced protein expression in the cells, causing inflammation through activation of uric acid transporters. [37][38][39] Chao, et al found that hs-CRP expression and insulin resistance were higher and LA diameter was larger in patients with a high SUA level. These findings indicated that increased inflammation and insulin resistance may be involved in the relationship between high SUA level and LA size.…”

Section: Hyperuricemia-induced Atrial Remodeling; Possible Mechanismsmentioning

confidence: 99%

“…51) Another report by Park, et al suggested that uric acid decreased eNOS activity and NO production through an impaired interaction between eNOS and CaM in endothelial cells. 52) As for the association between hyperuricemia and type 2 diabetes, Jia, et al and Zhang, et al reported that uric acid activated NF-κB as well as the AMPK and ERK signaling pathways, causing pancreatic β-cell dysfunction, 39,53) while pretreatment with UAT inhibitors could block the effects of uric acid. Zhi, et al reported that cardiac cells showed insulin resistance due to increased oxidative stress, when cells were exposed to high uric acid under in vitro and in vivo conditions.…”

Section: Intracellular Accumulation Of Uric Acid Causes Pathological mentioning

confidence: 99%

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Hyperuricemia and Atrial Fibrillation

2016

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SummaryThe importance of atrial fibrillation (AF) as a cause of mortality and morbidity has prompted research on its pathogenesis and treatment. Recognition of AF risk factors is essential to prevent it and reduce the risk of death. Hyperuricemia has been widely accepted to be associated with the incidence of paroxysmal or persistent AF, as well as to the risk of AF in post cardiovascular surgery patients. The possible explanations for this association have been based on their relation with either oxidative stress or inflammation. To investigate the link between hyperuricemia and AF, it is necessary to refer to hyperuricemia-induced atrial remodeling. So far, both ionic channel and structural remodeling caused by hyperuricemia might be plausible explanations for the occurrence of AF. Inhibition of xanthine oxidase and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, or the use of antioxidants, along with serum uric acid (SUA) level reduction to prevent inflammation, might be useful. Uric acid transporters (UATs) play a key role in the regulation of intracellular uric acid concentration. Intracellular rather than serum uric acid level is considered more important for the pathogenesis of AF. Identification of UATs expressed in cells is thus important, and targeting UATs might become a potential strategy to reduce the risk of hyperuricemia-induced atrial fibrillation. (Int Heart J 2016; 57: 395-399)

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“…Over-production of ROS impairs islet function (Koulajian et al, 2013;Lee et al, 2013) and decreases insulin secretion (Li et al, 2012;Barlow and Affourtit, 2013;Zhang et al, 2013). Thus, we measured insulin secretion in INS-1E cells.…”

Section: Berberine Increased Insulin Secretion In Ins-1e Cellsmentioning

confidence: 99%

Uncoupling protein‐2 mediates the protective action of berberine against oxidative stress in rat insulinoma INS‐1E cells and in diabetic mouse islets

Liu

Gao

et al. 2014

British J Pharmacology

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Background and PurposeUncoupling protein‐2 (UCP2) may regulate glucose‐stimulated insulin secretion. The current study investigated the effects of berberine, an alkaloid found in many medicinal plants, on oxidative stress and insulin secretion through restoration of UCP2 expression in high glucose (HG)‐treated INS‐1E cells and rat islets or in db/db mouse islets.Experimental ApproachMouse and rat pancreatic islets were isolated. Nitrotyrosine, superoxide dismutase (SOD)‐1 and UCP2 expression and AMPK phosphorylation were examined by Western blotting. Insulin secretion was measured by elisa. Mitochondrial reactive oxygen species (ROS) production was detected by confocal microscopy.Key ResultsIncubation of INS‐1E cells and rat islets with HG (30 mmol·L−1; 8 h) elevated nitrotyrosine level, reduced SOD‐1 and UCP2 expression and AMPK phosphorylation, and inhibited glucose‐stimulated insulin secretion. HG also increased mitochondrial ROS in INS‐1E cells. Co‐treatment with berberine inhibited such effects. The AMPK inhibitor compound C, the UCP2 inhibitor genipin and adenovirus ucp2 shRNA inhibited these protective effects of berberine. Furthermore, compound C normalized berberine‐stimulated UCP2 expression but genipin did not affect AMPK phosphorylation. Islets from db/db mice exhibited elevated nitrotyrosine levels, reduced expression of SOD‐1 and UCP2 and AMPK phosphorylation, and decreased insulin secretion compared with those from db/m+ mice. Berberine also improved these defects in diabetic islets and genipin blocked the effects of berberine.Conclusions and ImplicationsBerberine inhibited oxidative stress and restored insulin secretion in HG‐treated INS‐IE cells and diabetic mouse islets by activating AMPK and UCP2. UCP2 is an important signalling molecule in mediating anti‐diabetic effects of berberine.

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Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells

Cited by 108 publications

References 31 publications

Nox4 has a crucial role in uric acid-induced oxidative stress and apoptosis in renal tubular cells

Nox4 has a crucial role in uric acid-induced oxidative stress and apoptosis in renal tubular cells

Hyperuricemia and Atrial Fibrillation

Uncoupling protein‐2 mediates the protective action of berberine against oxidative stress in rat insulinoma INS‐1E cells and in diabetic mouse islets

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