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Hyperuricemia causes pancreatic ?-cell death and dysfunction through NF-?B signaling pathway.

ABSTRACT: Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic ?-cells. In this study, we examined the effects of uric acid on ?-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid-treated mice were markedly smaller in size and contained less insulin. Treatment of ?-cells in vitro with uric acid activated the NF-?B signaling pathway through I?B? phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid-treated mouse islets. These deleterious effects of uric acid on pancreatic ?-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11-7082, an NF-?B inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes ?-cell injury via the NF-?B-iNOS-NO signaling axis.

SUBMITTER: Jia L

PROVIDER: S-EPMC3808354 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway.

Jia Lu L Xing Jing J Ding Ying Y Shen Yachen Y Shi Xuhui X Ren Wei W Wan Meng M Guo Jianjin J Zheng Shujing S Liu Yun Y Liang Xiubin X Su Dongming D

PloS one 20131025 10

Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower ins ...[more]

PMID: 24205181

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Project description:BackgroundNasopharyngeal carcinoma (NPC) is a malignancy of the head and neck that is prevalent in Southeast Asia and southern China. Recent studies in epigenetics suggest that DNA methylation plays a pivotal role in the onset and progression of cancer. Combining the methyl-DNA binding domain capture technique and cDNA microarray analysis, we identified a unique hypermethylated gene, RERG (Ras-like estrogen-regulated growth inhibitor), that was down-regulated in NPC tissues. RERG is a tumor suppressor gene that was first reported in breast cancer. However, the functions of RERG are largely unknown in other tumor types.MethodsRERG expression was assessed in human subjects (NPC primary tissues and non-cancer tissues) and cell lines (NPC cell lines and an immortalized epithelial cell line NP460). Further, we investigated the methylation rate of RERG in both human subject and cell lines. 5-Aza-2'-deoxycytidine (Aza) or combined with trichostatin A (TSA) were treated to three NPC cell lines (HK1, C666-1 and HK1_EBV). In addition, the role of RERG in NPC cells and its underlying mechanisms were explored by overexpression of RERG in NPC cell lines.ResultsRERG was significantly down-regulated in NPC cancer nests compared to normal nasopharyngeal epithelium cells. Furthermore, the RERG promoter was frequently methylated in NPC tissues and cell lines. The RERG methylation rate yielded an area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.897 (95%CI: 0.818-0.976). The down-regulation of RERG was restored in NPC cells treated with Aza and TSA. In addition, ectopic expression of RERG in NPC cell lines resulted in a significant suppression of cell proliferation, clonogenicity, migration and invasion. RERG-overexpressing cells showed significantly slower growth and less angiogenesis in tumor xenografts in nude mice. RERG suppressed the ERK/NF-κB signaling pathway and inhibited tumor growth and angiogenesis with down-regulation of MMPs and IL8 in tumors of nude mouse xenografts.ConclusionsOur results suggest that RERG is frequently silenced by promoter CpG methylation in NPC, and acts as a functional tumor suppressor by suppressing the ERK/NF-κB signaling pathway. These findings support the potential use of RERG as a novel molecular target in NPC therapy.

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Hyperuricemia causes pancreatic ?-cell death and dysfunction through NF-?B signaling pathway.

Publications

Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway.

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