Accumulation of 8-Hydroxy-2′-Deoxyguanosine and Mitochondrial DNA Deletion in Kidney of Diabetic Rats

Kakimoto, Maiko; Inoguchi, Toyoshi; Sonta, Toshiyo; Hai, Yu; Imamura, Minako; Etoh, Takashi; Hashimoto, Toshihiko; Nawata, Hajime

doi:10.2337/diabetes.51.5.1588

Cited by 190 publications

(150 citation statements)

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“…STZ increased ROS and declined oxidation resistance in mice. In diabetes, excess ROS in the body attacks DNA and produces 8-OHdG as an indicator of DNA oxidative damage [26]. Our results showed 8-OHdG and MDA levels in T2D mice far beyond those in the normal group, which is consistent with the results by Pan et al [27].…”

Section: Discussionsupporting

confidence: 93%

Mulberry branch bark powder significantly improves hyperglycemia and regulates insulin secretion in type II diabetic mice

Yin

Liu

Zhang

2017

Food & Nutrition Research

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This experiment, based on the previous study on R. mori, introduces whole mulberry branch powder into the diet to treat diabetic mice. Mulberry branch bark powder (MBBP) was administered orally to streptozotocin (STZ)-induced type II diabetic (T2D) mice to investigate hypoglycemic effects. After a 4-week period of diet consumption containing 5%, 10% and 20% MBBP, the fasting blood glucose, body weight and the related western blotting were measured, pathologic and immunohistochemical were observed. The 20% MBBP group showed a significant reduction in hyperglycemia and hyperinsulinemia; fasting blood glucose and insulin decreased from 25.0 to 14.8 mmol/L and 26.5 to 16.0 mU/L, respectively. Pathologic and immunohistochemical observation showed that MBBP administration lead to the repair of pancreas cells and restoration of insulin secretion. Dietary MBBP was associated with the decrease in the contents of 3, 4-methylenedioxeamphetamine, 8-OHdG, aspartate aminotransferase, and alanine aminotransferase, and the increase in antioxidative ability and glucose tolerance. Western blotting (WB) analysis suggested that MBBP decreased the TNF-α levels, thus relieving inflammation and improving liver function. It also led to the downregulation of apoptosis factor expression. WB also confirmed that MBBP enhanced the gene expression of the key enzymes: insulin receptor, insulin receptor substrate, p-AKT, GSK3β, glycogen synthase, G6Pase and phosphoenolpyruvate carboxykinase, which are related to glucose metabolism in the liver, and increase the expression of the genes PDX-1, GLUT2, MafA, and glucokinase, related to insulin secretion. Thus, oral administration of MBBP regulated insulin secretion and effectively maintained normal levels of glucose metabolism in mice, which may be done by improving the antioxidant capacity and activating insulin signaling with T2D..

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Section: Discussionsupporting

confidence: 93%

Mulberry branch bark powder significantly improves hyperglycemia and regulates insulin secretion in type II diabetic mice

Yin

Liu

Zhang

2017

Food & Nutrition Research

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“…Notably, we first determined that the salivary 8-OHdG levels of periodontitis patients with deleted mtDNA were significantly higher than those of patients with non-deleted mtDNA and that there was a positive correlation between salivary 8-OHdG level and the occurrence of the 5-kbp mtDNA deletion in diseased gingival tissues. Similar correlations were previously reported by Kakimoto et al (Kakimoto et al 2002) and Suzuki et al (Suzuki et al 1999) in their studies on the association between oxidative DNA damage and diabetes.…”

Section: Discussionsupporting

confidence: 90%

“…Oxidative DNA damage is reported to be involved in the pathogenesis of many chronic conditions, including neurodegenerative disease (Wang et al 2008), diabetes (Kakimoto et al 2002), cancer (Wada et al 2006), and chronic inflammatory conditions (Dincer et al 2007). However, information on markers of ROS reactions with DNA in periodontitis is limited.…”

Section: Discussionmentioning

confidence: 99%

Increased salivary level of 8-hydroxydeoxyguanosine is a marker of premature oxidative mitochondrial DNA damage in gingival tissue of patients with periodontitis

Çanakçı

Tatar

et al. 2009

Arch. Immunol. Ther. Exp.

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Introduction: Oxidative stress may contribute to the pathogenesis of periodontitis. However, the detailed molecular mechanism remains unclear. Both 8-hydroxydeoxyguanosine (8-OHdG) and mitochondrial DNA (mtDNA) deletion have been reported as early oxidative DNA damage markers. In this study, 8-OHdG levels in saliva and mtDNA deletions in gingival tissue of patients with chronic periodontitis (CP) were evaluated. Materials and Methods: Gingival tissue and whole saliva samples were collected from 32 patients with CP and 32 healthy control subjects. To determine the clinical condition of each subject, the plaque index, gingival index, clinical attachment level (CAL), and probing depth (PD) were measured. Using the ELISA and polymerase chain reaction methods, the salivary 8-OHdG levels and the 7.4-kbp and 5-kbp mtDNA deletions were examined. Results: The 5-kbp mtDNA deletion was detected in 20 of the 32 periodontitis patients (62.5%), but was not detected in the healthy controls. The mean value of 8-OHdG in the saliva of the periodontitis patients with deleted mtDNA was significantly higher than in the patients with non-deleted mtDNA (p<0.01). Also, significant correlation was found between the occurrence of the 5-kbp mtDNA deletion and salivary 8-OHdG levels (p<0.01). Similar correlations were detected between salivary 8-OHdG levels and age, PD, and CAL (p<0.01, p<0.05). Conclusion: Increased oxidative stress may lead to premature oxidative DNA damage in the gingival tissue of periodontitis patients and the salivary 8-OHdG level may signify premature oxidative mtDNA damage in diseased gingival tissue.

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“…25 Additional studies have shown that urinary 8-OHdG correlated with the severity of DN and retinopathy 27 and also with future development of DN. 28 Others 29 have shown that in streptozotocin-induced diabetic rats, measurement of levels of 8-OHdG from mitochondrial DNA was higher in both renal cortices and papillae and so were the urinary 8-OHdG levels. In contrast, the levels of 8-OHdG in nuclear DNA were not elevated.…”

Section: Discussionmentioning

confidence: 99%

Diabetic Nephropathy Is Associated with Oxidative Stress and Decreased Renal Nitric Oxide Production

Prabhakar¹,

Starnes²,

Shi³

et al. 2007

Journal of the American Society of Nephrology

183

144

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The pathogenesis of diabetic nephropathy remains far from clear, partly due to the lack of a suitable animal model that mimics human renal disease in type 2 diabetes. In this study, the natural history of renal manifestations in ZSF 1 rats, a recently developed rodent model of type 2 diabetes, is described. Male ZSF 1 rats developed obesity and hyperglycemia by 20 weeks of age on a highcarbohydrate diet. They also developed systolic and diastolic hypertension, hypercholesterolemia, profound hypertriglyceridemia, proteinuria, and renal failure. Renal histology demonstrated changes consistent with early diabetic nephropathy, including arteriolar thickening, tubular dilation and atrophy, glomerular basement membrane thickening, and mesangial expansion. Furthermore, renal nitric oxide production was decreased, and homogenates from renal cortices demonstrated reduced expression of renal endothelial and inducible nitric oxide synthases. These changes were associated with increased urinary levels and renal expression of 8-hydroxydeoxyguanosine, an indicator of mitochondrial oxidative stress, as well as with increased renal peroxynitrite formation. Administration of either insulin or the antioxidant alpha-lipoic acid decreased proteinuria and oxidative stress, but only the former slowed progression of renal failure. We conclude that ZSF 1 rats represent the best available rat model to study nephropathy from type 2 diabetes and that the renal lesions are associated with increased oxidative stress and decreased renal nitric oxide availability. 18: 294518: -295218: , 200718: . doi: 10.1681 Despite several recent advances, the pathogenesis of diabetic nephropathy (DN) remains far from clear. 1 The lack of suitable diabetic animal models that develop nephropathy akin to human disease is a major barrier for progress in this field. Notwithstanding the contribution to mechanistic pathways, the in vitro models to study DN have compounded the problem, necessitating more dependable in vivo animal models. Furthermore, the growing epidemic of metabolic syndrome warrants need for animal models that develop hyperlipidemia and obesity in addition to maturity-onset diabetes to mimic complications of human diabetes and metabolic syndrome. We report here a genetically engineered rat that developed features of DN as well as full-blown metabolic syndrome. Furthermore, decreased renal nitric oxide (NO) production was noted in these rats, consistent with our previous observations in mesangial cell cultures in vitro that were exposed to high ambient glucose concentrations. These changes were associated with increased oxidative stress, which partly accounted for decreased NO levels. J Am Soc Nephrol

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Accumulation of 8-Hydroxy-2′-Deoxyguanosine and Mitochondrial DNA Deletion in Kidney of Diabetic Rats

Cited by 190 publications

References 49 publications

Mulberry branch bark powder significantly improves hyperglycemia and regulates insulin secretion in type II diabetic mice

Mulberry branch bark powder significantly improves hyperglycemia and regulates insulin secretion in type II diabetic mice

Increased salivary level of 8-hydroxydeoxyguanosine is a marker of premature oxidative mitochondrial DNA damage in gingival tissue of patients with periodontitis

Diabetic Nephropathy Is Associated with Oxidative Stress and Decreased Renal Nitric Oxide Production

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