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

Abstract

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,

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

“…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.…”

Diabetic Nephropathy: New Risk Factors and Improvements in Diagnosis

“…Elevated urinary levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of oxidative stress, predict the progression of diabetic nephropathy in patients with T2D [47]. Patients with T1D or T2D and with higher levels of proinflammatory cytokines and chemokines (interleukin 6, interleukin 18, and monocyte chemoattractant protein-1), high-sensitivity Creactive protein (hsCRP, a marker of subclinical inflammation), or adhesion molecules (soluble vascular cellular adhesion molecule-1 and soluble Eselectin) are at higher risk for developing nephropathy and for advancing to more severe kidney disease [48][49][50][51].…”

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

“…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. 73 The investigators of this study have concluded that erythropoietin may prevent microvascular damage in the diabetic retina.…”