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      Late Onset of Diabetic Nephropathy in Spontaneously Diabetic GK Rats

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      American Journal of Nephrology

      S. Karger AG

      Rat model, Type 2 diabetes, Nephropathy, Glomerulonephritis

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          Background/Aim: Prolonged exposure to hyperglycemia is one of the key factors to induce progressive diabetic nephropathy in humans. We examined whether or not the same phenomenon is observed in a nonobese type 2 diabetes model, in Goto-Kakizaki (GK) rats. Methods: Urine and serum samples from GK and Wistar rats were collected to measure biochemical parameters of the renal function. The kidneys of these animals were histopathologically and immunohistochemically analyzed. Results: Moderate hyperglycemia was sustained in GK rats during the experimental period. Noticeable morphological changes in the kidneys such as segmental glomerulosclerosis and tubulointerstitial fibrosis were observed only at 24 months of age. The expression of alpha smooth muscle actin and type IV collagen in glomeruli and tubulointerstitium was increased at 12 months of age and later. The macrophage infiltration was increased in parallel with the progression of renal lesions. The excretion of urinary protein in GK rats was increased only at 24 months of age. Moreover, the functional and morphological changes in Wistar rats were less severe than in age-matched GK rats. Conclusions: We conclude that renal changes of GK rats at a late stage were similar to those of progressive human diabetic nephropathy and that prolonged hyperglycemia may play a more crucial role in inducing progressive diabetic nephropathy than aging and obesity.

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          Most cited references 4

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          Activation of renal signaling pathways in db/db mice with type 2 diabetes.

          Altered regulation of signaling pathways may contribute to the pathogenesis of renal disease. We examined renal cortical signaling pathways in type 2 diabetes. The status of renal cortical signaling pathways was examined in control and db/db mice with type 2 diabetes in the early phase of diabetic nephropathy associated with renal matrix expansion and albuminuria. Tyrosine phosphorylation of renal cortical proteins was increased in diabetic mice. Renal cortical activities of phosphatidylinositol 3-kinase (PI 3-kinase) in antiphosphotyrosine immunoprecipitates, Akt (PKB), and ERK1/2-type mitogen-activated protein (MAP) kinase activities were significantly augmented sixfold (P < 0.01), twofold (P < 0.0003), and sevenfold (P < 0.001), respectively, in diabetic mice compared with controls. A part of the increased renal cortical PI 3-kinase activity was due to insulin receptor activation, as PI 3-kinase activity associated with beta chain of the insulin receptor was increased nearly fourfold (P < 0.0235). Additionally, the kinase activity of the immunoprecipitated insulin receptor beta chain was augmented in the diabetic renal cortex, and tyrosine phosphorylation of the insulin receptor was increased. In the liver, activities of PI 3-kinase in the antiphosphotyrosine immunoprecipitates and Akt also were increased threefold (P < 0.05) and twofold (P < 0.0002), respectively. However, there was no change in the hepatic insulin receptor-associated PI 3-kinase activity. Additionally, the hepatic ERK1/2-type MAP kinase activity was inhibited by nearly 50% (P < 0.01). These studies demonstrate that a variety of receptor signaling pathways are activated in the renal cortex of mice with type 2 diabetes, and suggest a role for augmented insulin receptor activity in nephropathy of type 2 diabetes.
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            Augmentation of kidney injury by basic fibroblast growth factor or platelet-derived growth factor does not induce progressive diabetic nephropathy in the Goto Kakizaki model of non-insulin-dependent diabetes

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              • Abstract: not found
              • Article: not found

              Effect of High Dietary Fat on Insulin Secretion in Genetically Diabetic Goto-Kakizaki Rats


                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                October 2003
                08 September 2003
                : 23
                : 5
                : 334-342
                Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan
                72915 Am J Nephrol 2003;23:334–342
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 9, Tables: 1, References: 28, Pages: 9
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                Original Article: Laboratory Investigation

                Cardiovascular Medicine, Nephrology

                Type 2 diabetes, Nephropathy, Glomerulonephritis, Rat model


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