Evaluation of Urinary 8-Hydroxydeoxy-Guanosine as a Novel Biomarker of Macrovascular Complications in Type 2 Diabetes

Nishikawa, Takeshi; Sasahara, Takayuki; Kiritoshi, Shinsuke; Sonoda, Kazuhiro; Senokuchi, Takahumi; Matsuo, Tomoko; Kukidome, Daisuke; Wake, Nakayasu; Matsumura, Takeshi; Miyamura, Nobuhiro; Sakakida, Michiharu; Kishikawa, Hiroki; Araki, Eiichi

doi:10.2337/diacare.26.5.1507

Cited by 175 publications

(134 citation statements)

References 26 publications

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“…When such damaged DNA is repaired, 8-OHdG is produced and excreted unchanged in the urine. 15 Previous studies 16 in experimental diabetes demonstrated decreased renal NO levels as a consequence of increased oxidative stress, primarily as a result of enhanced expression of superoxide dismutase and catalase. In those studies, NOS expression was not studied.…”

Section: Discussionmentioning

confidence: 98%

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

184

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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Section: Discussionmentioning

confidence: 98%

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

184

144

View full text Add to dashboard Cite

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“…8-OHdG is an accepted indicator of oxidative DNA damage, and its levels in serum and urine have been widely measured to monitor the degree of oxidative stress. 14,15 Plasma/serum NT levels have been used as a marker of oxidative and nitrosative stress and as a specific indicator of systemic peroxynitrite formation. 16,17 It should be noted that in the present study the levels of serum and urinary 8-OHdG and serum NT were higher in the diabetic patients with microalbuminuria than in those with normoalbuminuria, despite comparable levels of hyperglycemia.…”

Section: Discussionmentioning

confidence: 99%

Reduction of circulating superoxide dismutase activity in type 2 diabetic patients with microalbuminuria and its modulation by telmisartan therapy

Fujita

Sakamoto²,

Komatsu³

et al. 2011

Hypertens Res

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Growing evidence indicates that oxidative stress induced by excessive superoxide has a central role in the pathogenesis of diabetic nephropathy (DN). Telmisartan, one of the currently available angiotensin II type 1 receptor blockers (ARBs), has been shown to exert a more powerful proteinuria (albuminuria) reduction in patients with DN, but whether the prominent renoprotective effect of telmisartan is mediated through enhancing antioxidant defense capacity and reducing oxidative stress has not been fully elucidated. The present study first revealed that the serum activity of superoxide dismutase (SOD) responsible for superoxide removal is reduced in the DN stage of microalbuminuria, but not in normoalbuminuria in type 2 diabetic patients. We next examined the alteration of SOD and oxidative stress following an 8-week treatment with telmisartan (40 mg per day) in 12 type 2 diabetic patients with microalbuminuria. Interestingly, the telmisartan treatment not only reduced the circulating levels of two oxidative stress markers, 8-hydroxy-2¢-deoxyguanosine (8-OHdG) and nitrotyrosine (NT), but also enhanced serum SOD activity. Notably, a significant correlation was observed between the increase in serum SOD activity and the reduction in albuminuria. We further compared the anti-oxidative effect of telmisartan with that of losartan, another member of the ARB class, by implementing an 8-week interval crossover treatment with these ARBs in another 12 microalbuminuric type 2 diabetic patients. The patients showed higher serum SOD activity, and lower circulating levels of 8-OHdG and NT, during treatment with telmisartan than with losartan. These results suggest that telmisartan has a more potent antioxidative effect through its ability to enhance SOD activity in type 2 diabetic patients with microalbuminuria.

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“…From these clinical trials, it is possible that a pancreatic effect of GKAs could not be expected when pancreatic beta cells have been impaired. It is well known that the level of 8-hydroxydeoxyguanosine, a marker of oxidative stress, is increased in diabetic patients and independently associated with mean HbA 1c [31]; in addition, increased oxidative stress influences beta cell function, and antioxidant treatment can exert beneficial effects in diabetes, with a preservation of beta cell function [32]. We therefore investigated the effect of oxidative stress on GKA-induced changes in the expression of genes involved in beta cell function and proliferation.…”

Section: P22 Phox Expression (Au)mentioning

confidence: 99%

Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions

et al. 2012

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Aims/hypothesis We investigated changes in the expression of genes involved in beta cell function and proliferation in mouse islets stimulated with glucokinase activator (GKA) in order to elucidate the mechanisms by which GKA stimulates beta cell function and proliferation. Methods Islets isolated from mice were used to investigate changes in the expression of genes related to beta cell function and proliferation stimulated by GKA. In addition, Irs2 knockout (Irs2 −/− ) mice on a high-fat diet or a high-fat diet containing GKA were used to investigate the effects of GKA on beta cell proliferation in vivo. Results In wild-type mice, Irs2 and Pdx1 expression was increased by GKA. In Irs2 −/− mice, GKA administration increased the glucose-stimulated secretion of insulin and Pdx1 expression, but not beta cell proliferation. It was particularly noteworthy that oxidative stress inhibited the upregulation of the Irs2 and Pdx1 genes induced by GKA. Moreover, whereas neither GKA alone nor exendin-4 alone upregulated the expression of Irs2 and Pdx1 in the islets of db/db mice, prior administration of exendin-4 to the mice caused GKA to increase the expression of these genes.Conclusions/interpretation GKA-stimulated IRS2 production affected beta cell proliferation but not beta cell function. Oxidative stress diminished the effects of GKA on the changes in expression of genes involved in beta cell function and proliferation. A combination of GKA and an incretin-related agent might therefore be effective in therapy.

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Evaluation of Urinary 8-Hydroxydeoxy-Guanosine as a Novel Biomarker of Macrovascular Complications in Type 2 Diabetes

Cited by 175 publications

References 26 publications

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

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

Reduction of circulating superoxide dismutase activity in type 2 diabetic patients with microalbuminuria and its modulation by telmisartan therapy

Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions

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