Late Onset of Diabetic Nephropathy in Spontaneously Diabetic GK Rats

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Abstract

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

D Feliers, Hanna Abboud, Balakuntalam S. Kasinath … (2001)

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.

S G Riley, R Steadman, J D Williams … (1999)

Diabetes is now the most common cause of kidney failure. The pathogenesis of diabetic nephropathy in both type 1 and type 2 diabetes, however, is still incompletely understood. Two mechanisms postulated to contribute to the pathogenesis of progressive diabetic nephropathy are glomerular cell proliferation and glomerular visceral epithelial cell or podocyte injury. The aim of the current study was to determine whether the aggravation of mesangial cell injury or podocyte injury in isolation would induce progressive diabetic nephropathy. Specifically, we examined whether the administration of either platelet-derived growth factor (PDGF) or basic fibroblast growth factor (bFGF) in sub-nephritogenic doses might lead to an aggravation of kidney structural changes associated with hyperglycemia, resulting in progressive kidney damage in the Goto Kakizaki (GK) rat, which is a genetic model of non-obese non-insulin-dependent diabetes mellitus (NIDDM), in which progressive kidney disease does not develop spontaneously. The results demonstrate that the administration of PDGF to hyperglycemic GK rats led to acute mesangial cell proliferation and activation as assessed by 5-bromo-2'-deoxyuridine-positive nuclei and immunostaining for alpha-smooth muscle actin. Despite acute mesangial cell activation and proliferation, PDGF treatment had no long-term effect on either kidney structure or function. Similarly, treatment of GK rats with bFGF, despite the augmentation of podocyte injury as demonstrated by de novo expression of glomerular desmin expression, did not lead to the development of progressive diabetic nephropathy. In summary, the data in the current manuscript suggest that the additive effect of hyperglycemia and superimposed isolated mesangial cell or podocyte injury does not lead to progressive diabetic nephropathy. This further emphasises the multifactorial nature of the pathogenesis of progressive diabetic nephropathy.