Thioredoxin-interacting Protein Mediates High Glucose-induced Reactive Oxygen Species Generation by Mitochondria and the NADPH Oxidase, Nox4, in Mesangial Cells

Shah, Amar; Xia, Ling; Goldberg, Harry; Lee, Ken W.; Quaggin, Susan E.; Fantus, I. George

doi:10.1074/jbc.m112.419101

Cited by 129 publications

(125 citation statements)

References 76 publications

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“…Down-regulation of cellular and mitochondrial Nox4 with siRNA prevents Ang II-induced increase in mitochondrial superoxide production, identifying Nox4 as a prominent source of mitochondrial ROS in MCs treated with Ang II. These data are in agreement with the recent findings showing that high glucose and Ang II enhance mitochondrial Nox4 expression and the subsequent increase in ROS generation in renal cells (21)(22)(23).…”

Section: Discussionsupporting

confidence: 93%

Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

Lee¹,

Wauquier²,

Eid³

et al. 2013

Journal of Biological Chemistry

114

105

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Background: Oxidative stress is critical for the fibrotic response of mesangial cells (MCs) to angiotensin II. Results: Nox4-and mitochondrial reactive oxygen species (ROS)-dependent endothelial nitric-oxide synthase (eNOS) uncoupling led to fibronectin accumulation in MCs stimulated by angiotensin II. Conclusion: The Nox4/mitochondrial ROS/eNOS pathway mediates angiotensin II-induced MC injury. Significance: Targeting Nox4 and mitochondrial ROS is a promising therapeutic approach.

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Section: Discussionsupporting

confidence: 93%

Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

Lee¹,

Wauquier²,

Eid³

et al. 2013

Journal of Biological Chemistry

114

105

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“…Importantly, our experiments with THP1 cells cultured under various HG/NG conditions revealed an association between persistent DNA-me triggered by prior history of HG exposure and enhanced TXNIP expression in response to HG in vitro. We, thus, speculate that transient hyperglycemic episodes during the EDIC Study would induce more TXNIP overexpression and cellular dysfunction in cases vs. controls because of TXNIP hypo-me, which is in line with the reported adverse cellular roles of TXNIP (43)(44)(45)48). This type of cellular response to episodic HG provides mechanistic information toward understanding the connections between persistent DNA hypo-me at TXNIP and its gene expression and hence, metabolic memory of diabetic complications.…”

Section: Discussionsupporting

confidence: 66%

“…Persistence of DNA hypo-me in TXNIP at two time periods was particularly interesting, because TXNIP is a reported sensor of glucose stress, a prooxidant, and a proapoptotic protein, with gene expression that is highly associated with hyperglycemia and diabetic complications, including retinopathy and nephropathy (43)(44)(45), both of which were prevalent in our case group. TXNIP expression is highly induced by HG in various cell types (46)(47)(48), which by inhibiting thioredoxin, subsequently causes oxidative stress and apoptosis.…”

Section: Resultsmentioning

confidence: 90%

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Chen

Miao

Paterson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

196

185

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We examined whether persistence of epigenetic DNA methylation (DNA-me) alterations at specific loci over two different time points in people with diabetes are associated with metabolic memory, the prolonged beneficial effects of intensive vs. conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term followup Epidemiology of Diabetes Interventions and Complications (EDIC) Study. We compared DNA-me profiles in genomic DNA of whole blood (WB) isolated at EDIC Study baseline from 32 cases (DCCT conventional therapy group subjects showing retinopathy or albuminuria progression by EDIC Study year 10) vs. 31 controls (DCCT intensive therapy group subjects without complication progression by EDIC year 10). DNA-me was also profiled in blood monocytes (Monos) of the same patients obtained during EDIC Study years 16-17. In WB, 153 loci depicted hypomethylation, and 225 depicted hypermethylation, whereas in Monos, 155 hypomethylated loci and 247 hypermethylated loci were found (fold change ≥1.3; P < 0.005; cases vs. controls). Twelve annotated differentially methylated loci were common in both WB and Monos, including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications. A set of differentially methylated loci depicted similar trends of associations with prior HbA1c in both WB and Monos. In vitro, high glucose induced similar persistent hypomethylation at TXNIP in cultured THP1 Monos. These results show that DNA-me differences during the DCCT persist at certain loci associated with glycemia for several years during the EDIC Study and support an epigenetic explanation for metabolic memory.T he landmark Diabetes Control and Complications Trial (DCCT; 1983-1993 clearly showed that intensive (INT) glycemic control profoundly reduces the development and progression of microvascular complications in type 1 diabetes (T1D). The DCCT participants were subsequently followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study (1994 to present), during which all subjects were advised to practice INT treatment. Surprisingly, those previously assigned to conventional (CONV) therapy continued to develop complications, such as nephropathy, retinopathy, and macrovascular diseases, at significantly higher rates than the previous INT therapy group, despite nearly similar HbA1c levels during the EDIC Study (1-3). This persistence of benefit from early application of INT therapy, called "metabolic memory," is an enigma in the field of T1D: recent studies have suggested the involvement of epigenetic mechanisms (4-9).Epigenetics is the study of mostly heritable changes in gene expression and phenotype that occur without alterations in the underlying DNA sequence. Epigenetic states are affected by environmental factors, such as aberrant nutrition and metabolic states (4, 6-8, 10). DNA methylation (DNA-me; the classic epigenetic mark) and posttranslational modifications (PTMs) of histo...

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“…14 In addition, we recently reported that TxNIP enhances HG-induced mitochondria-derived O 2 2 (superoxide) as well as cellular ROS, at least in part, by augmenting the mitochondrial and cytosolic NADPH oxidase isoform, Nox4, in cultured mesangial cells. 15 Thus, by increasing the generation and decreasing the degradation of ROS, HG-induced TxNIP may contribute to glucotoxicity, as observed by others and our group in pancreatic b cells. 13,16,17 To elucidate the role of TxNIP in the pathogenesis of DN in vivo, we explored the action of TxNIP in the diabetic kidney of wild-type (WT) and TxNIP 2/2 (knockout [KO]) mice.…”

supporting

confidence: 60%

“…15 BPs were lower in both diabetic groups, likely reflecting a degree of volume contraction due to fluid loss ( Table 2).…”

Section: Txnip Deficiency Prevents Albuminuria In Stz-induced Diabetementioning

confidence: 99%

Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy

Shah

Xia

Masson

et al. 2015

Journal of the American Society of Nephrology

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Expression of thioredoxin-interacting protein (TxNIP), an endogenous inhibitor of the thiol oxidoreductase thioredoxin, is augmented by high glucose (HG) and promotes oxidative stress. We previously reported that TxNIP-deficient mesangial cells showed protection from HG-induced reactive oxygen species, mitogenactivated protein kinase phosphorylation, and collagen expression. Here, we investigated the potential role of TxNIP in the pathogenesis of diabetic nephropathy (DN) in vivo. Wild-type (WT) control, TxNIP 2/2 , and TxNIP +/2 mice were rendered equally diabetic with low-dose streptozotocin. In contrast to effects in WT mice, diabetes did not increase albuminuria, proteinuria, serum cystatin C, or serum creatinine levels in TxNIP 2/2 mice. Whereas morphometric studies of kidneys revealed a thickened glomerular basement membrane and effaced podocytes in the diabetic WT mice, these changes were absent in the diabetic TxNIP 2/2 mice. Immunohistochemical analysis revealed significant increases in the levels of glomerular TGF-b1, collagen IV, and fibrosis only in WT diabetic mice. Additionally, only WT diabetic mice showed significant increases in oxidative stress (nitrotyrosine, urinary 8-hydroxy-2-deoxy-guanosine) and inflammation (IL-1b mRNA, F4/80 immunohistochemistry). Expression levels of Nox4-encoded mRNA and protein increased only in the diabetic WT animals. A significant loss of podocytes, assessed by Wilms' tumor 1 and nephrin staining and urinary nephrin concentration, was found in diabetic WT but not TxNIP 2/2 mice. Furthermore, in cultured human podocytes exposed to HG, TxNIP knockdown with siRNA abolished the increased mitochondrial O 2 2 generation and apoptosis. These data indicate that TxNIP has a critical role in the progression of DN and may be a promising therapeutic target.

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Thioredoxin-interacting Protein Mediates High Glucose-induced Reactive Oxygen Species Generation by Mitochondria and the NADPH Oxidase, Nox4, in Mesangial Cells

Cited by 129 publications

References 76 publications

Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy

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