Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

Lal, Mark; Körner, Anna; Matsuo, Yosuke; Zelenin, Sergey; Cheng, Shuk Kei; Jaremko, Georg; DiBona, G. F.; Eklöf, Ann-Christine; Aperia, Anita

doi:10.2337/diabetes.49.8.1381

Cited by 70 publications

(59 citation statements)

References 41 publications

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“…Treatment with antioxidants is thought to improve the hyperglycaemia-attenuated anti-oxidative mechanisms by scavenging enzymes and antioxidant substances [2,3]. In animal models, diabetic nephropathy was successfully improved or ameliorated by a treatment with anti-oxidants, such as taurine, vitamin E and alpha-lipoic acid [18,19]. In a human clinical study, high-dose vitamin E supplementation normalizes creatinine clearance in patients with Type I diabetes [20].…”

Section: Discussionmentioning

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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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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Section: Discussionmentioning

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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“…Additional support comes from studies in which antioxidants prevent glomerular and renal hypertrophy, albuminuria, glomerular expression of TGF-␤1 and extracellular matrix, and PKC activation in experimental diabetes (64,65,(67)(68)(69)(70)(71). Reddi et al (72) showed that a selenium-deficient diet caused an increase in albuminuria, glomerular sclerosis, and plasma glucose levels in both normal and diabetic rats; that TGF-␤1 is a pro-oxidant; and that selenium deficiency increases oxidative stress via this growth factor.…”

Section: Oxidant Mechanisms In Diabetesmentioning

confidence: 99%

“…• glomeruli isolated from diabetic rats have increased production of oxidants including superoxide and H 2 O 2 (51,52,54) • antioxidants prevent functional and morphologic changes of diabetes (54,64,65,(67)(68)(69)(70)(71) • in vivo inhibition of Nox4 by antisense reduced whole-kidney and glomerular hypertrophy accompanied by reduced expression of fibronectin protein (95) • selenium-deficient diet causes an increase in albuminuria, glomerular sclerosis in diabetic rats, and an increase in TGF-␤1 (72) Human studies…”

Section: Oxidant Mechanisms In Diabetesmentioning

confidence: 99%

Oxidants in Chronic Kidney Disease

Shah

Baliga

Rajapurkar

et al. 2007

Journal of the American Society of Nephrology

238

186

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Chronic kidney disease is a worldwide public health problem that affects approximately 10% of the US adult population and is associated with a high prevalence of cardiovascular disease and high economic cost. Chronic renal insufficiency, once established, tends to progress to end-stage kidney disease, suggesting some common mechanisms for ultimately causing scarring and further nephron loss. This review defines the term reactive oxygen metabolites (ROM), or oxidants, and presents the available experimental evidence in support of the role of oxidants in diabetic and nondiabetic glomerular disease and their role in tubulointerstitial damage that accompanies progression. It concludes by reviewing the limited human data that provide some proof of concept that the observations in experimental models may be relevant to human disease.

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“…In addition, some authors have described significant hyperglycemia-induced increases in SOD activity [15][16][17]. However, the results have differed and some controversy still exists [8,12,14]. In the present study, this compensatory induction was hindered, probably as a result of rapid and severe hyperglycemia.…”

Section: Discussionmentioning

confidence: 43%

“…It is known that hyperglycemia can influence the expression and activity of important antioxidative enzymes, including superoxide dismutase [10][11][12][13][14][15][16][17]. In one previous experiment, the ability of renal cells to respond to glucose-induced oxidative stress by increasing levels of SOD mRNA was confirmed [11].…”

Section: Introductionmentioning

confidence: 83%

DNA oxidation and superoxide dismutase in the kidney of diabetic animals: effects of pioglitazone and repaglinide

et al. 2006

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Abstract:In the present study, DNA oxidative damage was elevated and superoxide dismutase (Cu,Zn-SOD) metabolism was disturbed in the kidney of alloxan-induced diabetic animals. The effects of pioglitazone and repaglinide, new oral antidiabetics, on 8-hydroxy-2'-deoxyguanosine (8-OHdG) and Cu,Zn-SOD were studied. Diabetic versus control levels (mean ± SE) of 8-OHdG were 24.9 ± 0.2 vs. 21.8 ± 0.1 and 21.5 ± 0.2 vs 20.1 ± 0.2 pmol/µg DNA after 4 and 8 weeks, respectively. At p<0.05, pioglitazone diminished this parameter in diabetic animals (22.0 ± 0.2 and 20.1 ± 0.3 pmol/µg DNA). The level was not affected in diabetic groups receiving repaglinide (24.9 ± 0.2 and 21.5 ± 0.3 pmol/µg DNA). In diabetic kidney, Cu,Zn-SOD mRNA was diminished relative to control animals and was modulated by pioglitazone and repaglinide treatments. Simultaneously, Cu,Zn-SOD activity was also diminished (1.5 ± 0.2 vs. 2.8 ± 0.3 and 1.8 ± 0.1 vs 2.9 ± 0.3 U/mg protein after 4 and 8 weeks, respectively) and partly changed after pioglitazone (2.1 ± 0.4 and 2.3 ± 0.3 U/mg protein) and repaglinide (2.0 ± 0.1 and 2.4 ± 0.2 U/mg protein). These results suggest that a reduction in oxidative stress in diabetic kidney can be achieved with the administration of pioglitazone and to some extent using repaglinide treatment.

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Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

Cited by 70 publications

References 41 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

Oxidants in Chronic Kidney Disease

DNA oxidation and superoxide dismutase in the kidney of diabetic animals: effects of pioglitazone and repaglinide

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