Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195

Aims/hypothesis An increasing amount of evidence indicates that mannose-binding lectin (MBL) plays a role in the development of diabetic nephropathy. The main objective of the study was to analyse whether MBL influences the effects of diabetes on the kidneys. Materials and methods In one group of wild-type mice and in one group of MBL double knockout mice we induced diabetes by the use of streptozotocin as a model of type 1 diabetes. Two groups of non-diabetic mice, wild-type and MBL knockout, were also included. By two-way ANOVA we evaluated if MBL modulated the effects of diabetes by testing the interaction between diabetes and MBL. Results MBL interacted with the effects of diabetes on three outcome measures: kidney weight (p<0.001), urinary albumin excretion (p=0.001) and the expression of collagen IVα1 (Col4a1) mRNA (p=0.002). This means that the effects that diabetes normally has on these parameters were significantly modified by MBL. MBL showed a tendency to interact with the effects of diabetes on glomerular basement membrane thickness and total mesangial volume (p=0.065 and p=0.063, respectively). Glomerular volume and total mesangial volume were significantly smaller in animals lacking MBL than in wild-type animals (p=0.006 and p=0.047, respectively). Conclusions/interpretation These findings, for the first time, show that the degree of kidney alteration as a consequence of diabetes is modified by MBL. These findings support a pivotal role of MBL in the development of diabetic kidney disease.

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“…in the STZ-diabetic rat [26][27][28][29][30]. In these studies the most pronounced upregulation was observed in the early stages of the disease.…”

Section: Discussionmentioning

confidence: 69%

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

et al. 2007

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“…In the recent study in OLETF rats described above [114], renal VEGF mRNA and glomerular VEGF immunoreactivity was reported to be increased over a diabetes duration of 9 to 68 weeks [114]. In another purely descriptive study, changes in renal VEGF concentrations were described in STZ-diabetic rats with a diabetes duration of 3 and 32 weeks [132].…”

Section: In Vitro Evidence For Vegf Effects On Kidney Cellsmentioning

confidence: 92%

“…In the study described above in an animal model of Type II diabetes [114], it was shown that long-term AGEinhibitor (OPB-9195) treatment of diabetic animals abolished the enhanced renal VEGF mRNA and glomerular VEGF immunoreactivity along with renoprotection, by restoring diabetes-induced renal collagen IV accumulation to normal and reducing the rise in AER [114].…”

Section: Agents With Effect On the Altered Vegf Axis In Diabetic Kidnmentioning

confidence: 98%

“…Inan experimental model of Type II diabetes [the Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat] renal TGF-b1 mRNA and glomerular TGF-b1 immunoreactivity was reported to be increased over a diabetes duration of 9 to 68 weeks [114]. Oral treatment with a new AGE-inhibitor (OPB-9195) for up to 68 weeks reduced the increased renal expressions of TGF-b1 mRNA and concentrations of protein to normal, along with restoring diabetes-associated renal collagen IV accumulation to normal and diminishing the increased AER [114].…”

Section: Advanced Glycation End-product (Age) Inhibitionmentioning

confidence: 99%

“…Oral treatment with a new AGE-inhibitor (OPB-9195) for up to 68 weeks reduced the increased renal expressions of TGF-b1 mRNA and concentrations of protein to normal, along with restoring diabetes-associated renal collagen IV accumulation to normal and diminishing the increased AER [114].…”

Section: Advanced Glycation End-product (Age) Inhibitionmentioning

confidence: 99%

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Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

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Pathogenesis of Diabetic Microvascular Complications

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International Textbook of Diabetes Mellitus

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Complications of diabetes have been the leading cause of mortality and morbidity in both type 1 and type 2 diabetes. Based on the sites of functional and pathological changes, these complications have been characterized as cardiomyopathy, macrovasculopathy, and microvasculopathy. Multiple clinical studies have shown that glycemic control is by far the most effective approach in the prevention of microvascular and neuropathic complications. However, tight glycemic control is still difficult to achieve using current available regimen, and therefore novel pathogenesis‐based interventions that can prevent and reverse the complications even in the presence of hyperglycemia are needed. Over the past decade, advances in molecular and cellular biological techniques have revealed many potential mechanisms utilized by hyperglycemia to induce its adverse effects. Several mechanisms, including vascular oxidative stress; formation of advanced glycation endproducts; activation of protein kinase C; increased flux through hexosamine pathway; inflammation‐induced vascular pathology; altered expression and actions of growth factors, cytokines, and vasomotor mediators; and increased flux through polyol pathway, have been studied in detail. The identification of such mechanisms has lead to the development of novel pharmacological approaches.

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Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195

Cited by 212 publications

References 61 publications

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

Pathogenesis of Diabetic Microvascular Complications

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