Oxidative DNA damage in diabetes mellitus: its association with diabetic complications

Hinokio, Yoshinori; Suzuki, Susumu; Hirai, Masashi; Chiba, Masaki; Hirai, Atsuko; Toyota, Takayoshi

doi:10.1007/s001250051258

Cited by 191 publications

(123 citation statements)

References 11 publications

(17 reference statements)

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“…SevThe link between hyperglycaemia and the complications of diabetes is still not clear. Increased oxidative stress in diabetes might contribute to the pathogenesis of diabetic complications, including nephropathy [2, eral reports described an increase in the 8-oxodG content in mononuclear cells and urine in Type I and Type II (non-insulin-dependent) diabetic patients [8,9,10]. We have reported a significant relation between the urinary or leukocyte 8-oxodG or both and the severity of diabetic nephropathy and retinopathy [1].…”

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confidence: 58%

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Urinary excretion of 8-oxo-7, 8-dihydro-2′-deoxyguanosine as a predictor of the development of diabetic nephropathy

et al. 2002

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Aims/hypothesis. The increased oxidative stress in diabetes is known to contribute to the progression of diabetes and its complications. We have reported a significant relation between the content of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), a product of oxidative DNA damage in urine or leukocytes and the severity of diabetic nephropathy and retinopathy [1]. We investigated whether 8-oxodG in urine or leukocytes is associated with the progression of diabetic nephropathy. Methods. We measured urinary 8-oxodG contents at entry and carried out a prospective longitudinal study to assess the progression of nephropathy over 5 years.Results. There was a significant progression of diabetic nephropathy in the patients with higher excretion of 8-oxodG in urine compared with the patients with moderate or lower excretion of 8-oxodG. There was no significant association between the leukocyte 8-oxodG contents and the development of nephropathy. The multivariate logistic regression analysis suggests that the urinary 8-oxodG was the strongest predictor of nephropathy among several known risk factors. Conclusion/interpretation. This study provides evidence that increased oxidative stress has a primary role in the pathogenesis of diabetic nephropathy. A local enhancement of oxidative stress in diabetic kidney might explain the possible linkage between the increased urinary excretion of 8-oxodG and the development of nephropathy. 8-oxodG in urine is a useful clinical marker to predict the development of diabetic nephropathy in diabetic patients. Oxidative stress is one of the important mediators of vascular complications in diabetes including nephropathy. The hyperglycaemia-induced generation of reactive oxygen species (ROS) is linked by three pathological pathways to diabetic complications: activation of protein kinase C (PKC), the formation of advanced glycation end products (AGE), and sorbitol accumulation [4,5]. Normalising mitochondrial ROS production was reported to block these hyperglycaemia-mediated signalling pathways.8-oxodG is a product of oxidative DNA damage following specific enzymatic cleavage after ROSinduced 8-hydroxylation of the guanine base in mitochondrial and nuclear DNA [6]. 8-oxodG is known to be a sensitive marker of oxidative DNA damage and of the total systemic oxidative stress in vivo [7]. SevThe link between hyperglycaemia and the complications of diabetes is still not clear. Increased oxidative stress in diabetes might contribute to the pathogenesis of diabetic complications, including nephropathy [2,

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confidence: 58%

“…The 8-oxodG samples from urine and leukocytes were prepared and analysed by high performance liquid chromatography with electro-chemical detection (HPLC-ECD) [10]. The urinary albumin concentration was measured by an enzymelinked immunosorbent assay.…”

Section: Methodsmentioning

confidence: 99%

Urinary excretion of 8-oxo-7, 8-dihydro-2′-deoxyguanosine as a predictor of the development of diabetic nephropathy

et al. 2002

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“…It has been shown that in type 2 diabetic patients with diabetic nephropathy and/or retinopathy, levels of 8-OHdG are significantly higher than in diabetic patients without these complications. 70,71 Furthermore, in a prospective study, it was demonstrated that in type 2 diabetic patients, higher levels of urinary 8-OHdG were associated with the progression of diabetic nephropathy. 72 A recent study demonstrated that low doses of erythropoietin inhibit oxidative stress and early vascular changes in the experimental diabetic retina.…”

Section: Contribution Of Inflammation and Oxidative Stress To Dr And mentioning

confidence: 99%

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

2011

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Diabetes and hypertension frequently coexist and constitute the most notorious combination for the pathogenesis of diabetic nephropathy and retinopathy. Large clinical trials have clearly demonstrated that tight control of glycemia and/or blood pressure significantly reduces the incidence and progression of diabetic retinopathy (DR) and nephropathy. However, the mechanism by which hypertension interacts with diabetes to induce and/or exacerbate nephropathy and retinopathy is very unclear. Substantial evidence implicates the involvement of chronic inflammation and oxidative stress in the pathogenesis of DR and nephropathy. In addition, hypertension causes oxidative stress and inflammation in the kidney and retina. In the present review, we summarized data obtained from our research along with those from other groups to better understand the role of hypertension in the pathogenesis of diabetic nephropathy and retinopathy. It is suggested that oxidative stress and inflammation may be common denominators of kidney and retinal damage in the concomitant presence of diabetes and hypertension.

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“…There is an increase in 8-oxodG levels in tissue of diabetic rats and in the urine of patients with type 1 and type 2 diabetes (13)(14)(15), with the levels being significantly higher in patients with albuminuria or with other diabetic complications (16). The steadystate level of 8-oxodG in DNA reflects its rate of generation and of repair.…”

Section: Conclusion-hyperglycemiamentioning

confidence: 99%

Mechanism of Oxidative DNA Damage in Diabetes

Simone

Gorin²,

Velagapudi³

et al. 2008

Diabetes

115

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OBJECTIVE-To investigate potential mechanisms of oxidative DNA damage in a rat model of type 1 diabetes and in murine proximal tubular epithelial cells and primary culture of rat proximal tubular epithelial cells. Akt and tuberin, levels, and 8-oxoG-DNA glycosylase (OGG1) expression were measured in kidney cortical tissue of control and type 1 diabetic animals and in proximal tubular cells incubated with normal or high glucose. RESEARCH DESIGN AND METHODS-Phosphorylation ofRESULTS-In the renal cortex of diabetic rats, the increase in Akt phosphorylation is associated with enhanced phosphorylation of tuberin, decreased OGG1 protein expression, and 8-oxodG accumulation. Exposure of proximal tubular epithelial cells to high glucose causes a rapid increase in reactive oxygen species (ROS) generation that correlates with the increase in Akt and tuberin phosphorylation. High glucose also resulted in downregulation of OGG1 protein expression, paralleling its effect on Akt and tuberin. Inhibition of phosphatidylinositol 3-kinase/ Akt significantly reduced high glucose-induced tuberin phosphorylation and restored OGG1 expression. Hydrogen peroxide stimulates Akt and tuberin phosphorylation and decreases OGG1 protein expression. The antioxidant N-acetylcysteine significantly inhibited ROS generation, Akt/protein kinase B, and tuberin phosphorylation and resulted in deceased 8-oxodG accumulation and upregulation of OGG1 protein expression.CONCLUSIONS-Hyperglycemia in type 1 diabetes and treatment of proximal tubular epithelial cells with high glucose leads to phosphorylation/inactivation of tuberin and downregulation of OGG1 via a redox-dependent activation of Akt in renal tubular epithelial cells. This signaling cascade provides a mechanism of oxidative stress-mediated DNA damage in diabetes. Diabetes

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Oxidative DNA damage in diabetes mellitus: its association with diabetic complications

Cited by 191 publications

References 11 publications

Urinary excretion of 8-oxo-7, 8-dihydro-2′-deoxyguanosine as a predictor of the development of diabetic nephropathy

Urinary excretion of 8-oxo-7, 8-dihydro-2′-deoxyguanosine as a predictor of the development of diabetic nephropathy

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

Mechanism of Oxidative DNA Damage in Diabetes

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