Catalase overexpression attenuates angiotensinogen expression and apoptosis in diabetic mice

Brezniceanu, Marie-Luise; Liu, F.; Wei, Chih‐Chang; Tran, Susan H; Sachetelli, Sébastien; Zhang, S.-L.; Guo, Deng Fu; Filep, János G.; Ingelfinger, Julie R.; Chan, John S.D.

doi:10.1038/sj.ki.5002188

Cited by 150 publications

(151 citation statements)

References 58 publications

(77 reference statements)

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“…The features of tubulointerstitial histopathology include inflammation and apoptosis, which are not necessarily secondary to glomerular lesions. 7,[24][25][26] In addition, tubular injury alone is believed to be closely correlate with clinical manifestations of DKD, including the extent albumin excretion and its degradation in tubules. The latter may serve as a primary key site for the development of DKD, because tubular injury has been described to be a better predictor in the progression of the renal disease.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Zhan

Usman

Sun

et al. 2015

Journal of the American Society of Nephrology

240

251

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Diabetic kidney disease (DKD) is associated with oxidative stress and mitochondrial injury. Myo-inositol oxygenase (MIOX), a tubular-specific enzyme, modulates redox imbalance and apoptosis in tubular cells in diabetes, but these mechanisms remain unclear. We investigated the role of MIOX in perturbation of mitochondrial quality control, including mitochondrial dynamics and autophagy/mitophagy, under highglucose (HG) ambience or a diabetic state. HK-2 or LLC-PK1 cells subjected to HG exhibited an upregulation of MIOX accompanied by mitochondrial fragmentation and depolarization, inhibition of autophagy/ mitophagy, and altered expression of mitochondrial dynamic and mitophagic proteins. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which coincided with increased reactive oxygen species generation, Bax activation, cytochrome C release, and apoptosis. Overexpression of MIOX in LLC-PK1 cells enhanced the effects of HG, whereas MIOX siRNA or D-glucarate, an inhibitor of MIOX, partially reversed these perturbations. Moreover, decreasing the expression of MIOX under HG ambience increased PTEN-induced putative kinase 1 expression and the dependent mitofusin-2-Parkin interaction. In tubules of diabetic mice, increased MIOX expression and mitochondrial fragmentation and defective autophagy were observed. Dietary supplementation of D-glucarate in diabetic mice decreased MIOX expression, attenuated tubular damage, and improved renal functions. Notably, D-glucarate administration also partially attenuated mitochondrial fragmentation, oxidative stress, and apoptosis and restored autophagy/mitophagy in the tubular cells of these mice. These results suggest a novel mechanism linking MIOX to impaired mitochondrial quality control during tubular injury in the pathogenesis of DKD and suggest D-glucarate as a potential therapeutic agent for the amelioration of DKD.

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Section: Discussionmentioning

confidence: 99%

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Zhan

Usman

Sun

et al. 2015

Journal of the American Society of Nephrology

240

251

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“…17 Recently, it has been reported that autophagy is modulated by multiple intracellular stresses, including oxidative stress. 30,31 To investigate whether TXNIP-mediated oxidative stress is involved in regulation of autophagy, nitrotyrosine, 32 a marker of NO-dependent oxidative stress, was examined in diabetic mice kidneys. Immnunohistochemical staining results confirmed that the expression of nitrotyrosine is significantly increased in diabetic mice compared with non-diabetic mice (Po0.05, Figures 9a and b).…”

Section: Txnip Mediates Hg-induced Dysfunction Of Tubular Autophagy Tmentioning

confidence: 99%

Thioredoxin-interacting protein mediates dysfunction of tubular autophagy in diabetic kidneys through inhibiting autophagic flux

Huang

Lin

Cheng

et al. 2014

Laboratory Investigation

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Thioredoxin-interacting protein (TXNIP) expression is ubiquitous and is induced by a variety of cellular stresses, including high intracellular glucose. TXNIP is associated with activation of oxidative stress and tubulointerstitial fibrosis in diabetic nephropathy. Autophagy is a major pathway that delivers damaged proteins and organelles to lysosomes to maintain cellular homeostasis. This study aimed to investigate the dysregulation of autophagy and the regulation of TXNIP on autophagy in renal proximal tubular cells (PTCs) under diabetic conditions. The formation of autophagosomes was measured using transmission electron microscopy, and LC3-II, and the effectiveness of autophagic clearance was determined by p62 expression in diabetic kidney and in human PTCs exposed to high glucose (HG). The results collectively demonstrated increased expression of TXNIP, LC3/LC3-II and p62 in renal tubular cells of mice with diabetic nephropathy and in cultured human PTCs exposed to HG (30 mM/l) for 48 h compared with control. The formation of autophagic vacuoles was increased in HG-induced cells. Furthermore, silencing of TXNIP by siRNA transfection reduced autophagic vacuoles and the expression of LC3-II and p62 in human PTCs exposed to HG compared with control and partially reversed the accumulation of LC3-II and p62 induced by bafilomycin A 1 (50 nM/l), a pharmacological inhibitor of autophagy which blocks the fusion of autophagosomes with lysosomes and impairs the degradation of LC3-II and p62. Collectively, these results suggest that hyperglycemia leads to dysfunction of autophagy in renal tubular cells and decreases autophagic clearance. HG-induced overexpression of TXNIP may contribute to the dysfunction of tubular autophagy in diabetes.

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“…ROS can activate several proinflammatory transcriptional factors, resulting in the production of cytokines, chemokines and adhesion molecules, as well as an influx of inflammatory cells into the kidney [4,5]. The importance of redox balance in diabetic nephropathy has been demonstrated in diabetic mice overexpressing antioxidant enzymes; these animals are protected from interstitial fibrosis and their proximal tubule cells do not undergo apoptosis [6][7][8][9]. Therefore, the preservation of antioxidant defence capacity in kidneys may be a major determinant of the severity of diabetic nephropathy caused by sustained hyperglycaemic oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity

et al. 2013

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Aims/hypothesis B cell CLL/lymphoma 2 (BCL-2)-interacting cell death suppressor (BIS), known as an anti-stress and antiapoptotic protein, has been reported to modulate susceptibility to oxidative stress. This study investigated the potential role of BIS as an antioxidant protein in diabetic nephropathy. Methods Diabetes was induced in BIS-heterozygote (BIS-HT) mice via streptozotocin injections and the resulting phenotypes were compared with those of BIS-wild-type (BIS-WT) mice over the 20 weeks following diabetes induction.Results Renal injuries, represented by increased plasma creatinine levels and increased albuminuria, were greater in diabetic BIS-HT mice than in diabetic BIS-WT mice, and were accompanied by a significant increase in reactive oxygen species (ROS) and oxidative stress markers. Moreover, renal pathological changes and the apoptotic process were accelerated in diabetic BIS-HT mice compared with diabetic BIS-WT mice with the same degree of hyperglycaemia; all were restored by 4-hydroxy-2,2,6,6-tetramethylpiperidine-Noxyl (tempol) treatment. The levels of NADPH oxidase and related proteins were not significantly higher in diabetic BIS-HT mice compared with diabetic BIS-WT mice. However, levels of superoxide dismutase (SOD)1 and SOD2 increased on the induction of diabetes in BIS-WT mice but not in BIS-HT mice, correlating with the total SOD activity. An in vitro study showed that knockdown of BIS production also resulted in impaired induction of SOD activity as well as SOD levels in HK-2 and NMS cells, concomitant with significant ROS accumulation. Conclusion/interpretation Our results suggest that the decreased antioxidant capacity of BIS aggravates diabetic nephropathy in diabetic BIS-HT mice, possibly as a result of the disruption in the regulation of SOD protein quality under oxidative stress. Electronic supplementary material The online version of this article (doi:10.1007/s00125-013-3064-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Catalase overexpression attenuates angiotensinogen expression and apoptosis in diabetic mice

Cited by 150 publications

References 58 publications

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Thioredoxin-interacting protein mediates dysfunction of tubular autophagy in diabetic kidneys through inhibiting autophagic flux

Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity

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