Localization of glycated proteins in the glomeruli of patients with diabetic nephropathy

Sakai, Hideto; Jinde, Kiichiro; Suzuki, Daisuke; Yagame, Mitsunori; Nomoto, Yasuo

doi:10.1093/ndt/11.supp5.66

Cited by 38 publications

(20 citation statements)

References 11 publications

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“…Chronic hyperglycemia results in the accumulation of advanced glycation end products (AGEs) in the body, which further increase the risk for vascular complications in patients with DM (31). A previous study demonstrated that AGEs are always present in diabetic individuals with kidney dysfunction, leading to the overproduction of ROS (32).…”

Section: Discussionmentioning

confidence: 99%

Metformin ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes

Zhang

et al. 2017

Experimental and Therapeutic Medicine

124

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Abstract. The present study aimed to explore the renoprotective effect of metformin on diabetic nephropathy in type 2 diabetic rats. A rat model of type 2 diabetic nephropathy (T2DN) was successfully induced via a high-fat diet combined with a single low-dose of streptozotocin. Metformin was administered intragastrically for 13 weeks, and fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), HDL-c, LDL-c, urinary and serum creatinine levels were subsequently examined at the end of administration. Renal function was determined after the treatment protocol. Expression levels of transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF) were assessed via immunohistochemical analysis. Superoxide dismutase activity, malondialdehyde content and glutathione peroxidase levels were assessed in kidney tissues using commercially available kits. The results of the present study demonstrated that metformin administration significantly decreased the levels of serum blood urea nitrogen, serum creatinine, creatinine clearance, urinary albumin excretion and fasting blood glucose in rats with T2DN. Furthermore, TG, TC and LDL-c levels were significantly decreased following metformin treatment, whereas HDL-c was increased. Metformin treatment significantly increased SOD activity and significantly decreased malondialdehyde levels, as compared with the model group. It was also demonstrated that metformin administration significantly decreased the expression levels of TGF-β1 and attenuated the morphological changes associated with T2DN in rats. These data clearly demonstrated the renoprotective effects of metformin against the development and progression of T2DN in rats. The underlying mechanism of this protective effect may be associated with glycemic control, lipid metabolism, and anti-oxidative and anti-inflammatory functions.

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Section: Discussionmentioning

confidence: 99%

Metformin ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes

Zhang

et al. 2017

Experimental and Therapeutic Medicine

124

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“…Administration of anti-glycated albumin antibody in animal models reduces plasma levels of glycated albumin, reduces AER, and reverses glomerular pathology (22). Human studies have been conflicting, perhaps in part because of small numbers and confounding by other risk factors, but one of the largest previous studies clearly indicated that Amadori albumin levels were elevated in individuals with nephropathy compared with individuals without nephropathy (15,(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Circulating and Urinary Transforming Growth Factor β1, Amadori Albumin, and Complications of Type 1 Diabetes

Chaturvedi¹,

Schalkwijk

Abrahamian

et al. 2002

Diabetes Care

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OBJECTIVE -Transforming growth factor (TGF)-␤1 is overexpressed in diabetes as a consequence of hyperglycemia and the creation of early glycated end products and may be responsible for the characteristic structural renal changes associated with diabetes. We sought to examine the role of both urinary and circulating TGF-␤1 and its promoter Amadori albumin in the vascular complications of type 1 diabetes. RESEARCH DESIGN AND METHODS -The present article reports on a nested casecontrol study from the EURODIAB Prospective Complications Study of Europeans with type 1 diabetes. Case subjects (n ϭ 356) were all individuals with one or more complications of diabetes; control subjects (n ϭ 185) were all individuals with no evidence of complications.RESULTS -Urinary TGF-␤1 and Amadori albumin were elevated in patients with micro-or macroalbuminuria. Standardized regression effects (SREs) for macroalbuminuria versus normoalbuminuria were 2.45 (95% CI 1.88 -3.18, P ϭ 0.0001 for urinary TGF-␤1) and 1.67 (1.34 -2.07, P ϭ 0.001 for Amadori albumin). The SRE for urinary TGF-␤1 remained statistically significant when adjusted for HbA 1c , Amadori albumin, and blood pressure. Circulating TGF-␤1 was elevated in individuals with proliferative retinopathy compared with individuals without retinopathy (SRE 1.29 [1.07-1.550], P ϭ 0.007). This result was attenuated to 1.16 (0.95-1.43, P ϭ 0.2) in the multivariate model, largely because of HbA 1c .CONCLUSIONS -Elevated levels of urinary TGF-␤1 in macroalbuminuria were associated with elevations in Amadori albumin and HbA 1c and also in blood pressure. In contrast, only circulating TGF-␤1 was related to proliferative retinopathy, and HbA 1c largely accounted for this. These findings may indicate novel pathways for understanding mechanisms and therapeutic interventions. Diabetes Care 25:2320 -2327, 2002I mprovements in glycemic control and the greater use of antihypertensive therapy should eventually have a beneficial impact on the incidence of severe nephropathy in type 1 diabetes. However, early disease, such as microalbuminuria and macroalbuminuria, will continue to occur because glycemic control cannot wholly prevent the progression of albuminuria, and there is currently little evidence that antihypertensive use in normotensive normoalbuminuric patients is of clinical value (1). Both microalbuminuria and macroalbuminuria significantly increase the risk of morbidity and mortality from coronary heart disease and are strong predictors of subsequent severe renal disease (2). Prevention of the early stages of diabetic renal disease and reduction in progression should now be priorities, but these steps require a more complete understanding of the etiology to identify suitable targets for intervention.Diabetic nephropathy is characterized by hypertrophy of the glomerular and tubuloepithelial structures and thickening of the glomerular and tubular basement membrane, due largely to the effects of hyperglycemia (3). The cytokine transforming growth factor (TGF)-␤1 appears to be a key mediator f...

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“…8 -11 A recent clinical study has clearly shown an association between Amadori albumin and diabetic vascular complications. [12][13][14] AGEs exert their effects on cells by interacting with specific cellular receptors, the best characterized of which is the receptor for AGE (RAGE). 15,16 It has been demonstrated that AGE-RAGE interaction-mediated induction of cellular oxidant stress triggers a cascade of intracellular signals involving p21 ras and mitogen-activated protein kinase (MAPK), culminating in transcription factor activation.…”

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confidence: 99%

Vascular Smooth Muscle Cell Activation by Glycated Albumin (Amadori Adducts)

et al. 2002

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Abstract-Nonenzymatic glycation is increased in diabetes. The role of advanced glycation end products has been implicated in many of the complications of diabetes, whereas the effects of early-glycation Amadori-modified proteins on vascular cells alone are poorly defined. In the present study, we show that glycated serum albumin (GSA) induces a parallel activation of the redox-responsive transcription factors (nuclear factor B) and AP-1 and increases activity of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38 MAPK in vascular smooth muscle cells (VSMCs). GSA increased expression of early response genes, c-fos and c-jun, and inflammatory genes, monocyte chemoattractant peptide (MCP-1), and interleukin (IL)-6. These effects were comparable to bacterial lipopolysaccharide, tumor necrosis factor-␣, (TNF-␣), IL-1␤, angiotensin II, epidermal growth factor, and the phorbol ester PMA. One of signaling pathways by which GSA activates VSMCs appears to be via nuclear factor B activation, leading to induction of MCP-1 and IL-6 gene expression, comparable to the effects of lipopolysaccharide, TNF-␣, and IL-1␤. Another signaling cascade by which GSA activates VSMCs is the ERK3c-Fos3 AP-1 pathway, which may lead to stimulation of cell proliferation and migration. These effects are comparable to the effects of angiotensin II, epidermal growth factor, and PMA. Incubation of VSMCs with the antioxidant N-acetylcysteine suppressed GSA-elicited mRNA induction of MCP-1 and IL-6. Inhibition of p38 MAPK but not ERK caused attenuation of MCP-1 and IL-6 mRNA induction. Finally, GSA caused a significant stimulation of VSMC growth and migration. These findings suggest that GSA may play a role in diabetic atherogenesis by activating VSMCs, leading to induction of inflammatory mediators in the vessel wall, as well as proliferation and migration of VSMCs. (Hypertension. 2002;39:22-28.)

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Localization of glycated proteins in the glomeruli of patients with diabetic nephropathy

Cited by 38 publications

References 11 publications

Metformin ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes

Metformin ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes

Circulating and Urinary Transforming Growth Factor β1, Amadori Albumin, and Complications of Type 1 Diabetes

Vascular Smooth Muscle Cell Activation by Glycated Albumin (Amadori Adducts)

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