Characterization of diabetic nephropathy in CaM kinase IIα (Thr286Asp) transgenic mice (original) (raw)
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Diabetologia, 2011
Aims/hypothesis The activation of platelet-derived growth factor receptor-β (PDGFR-β) signalling is increased in the glomeruli and tubules of diabetic animals. In this study, we examined the role of PDGFR-β signalling during the development of diabetic nephropathy. Methods We recently generated pancreatic beta cell-specific Ca 2+ /calmodulin-dependent protein kinase IIα (Thr286Asp) transgenic mice (CaMKIIα mice), which show very high plasma glucose levels up to 55.5 mmol/l and exhibit the features of diabetic nephropathy. These mice were crossed with conditional knockout mice in which Pdgfr-β (also known as Pdgfrb) was deleted postnatally. The effect of the deletion of the Pdgfr-β gene on diabetic nephropathy in CaMKIIα mice was evaluated at 10 and 16 weeks of age. Results The plasma glucose concentrations and HbA 1c levels were elevated in the CaMKIIα mice from 4 weeks of age. Variables indicative of diabetic nephropathy, such as an increased urinary albumin/creatinine ratio, kidney weight/body weight ratio and mesangial area/glomerular area ratio, were observed at 16 weeks of age. The postnatal deletion of the Pdgfr-β gene significantly decreased the urinary albumin/creatinine ratio and mesangial area/glomerular area ratio without affecting the plasma glucose concentration. Furthermore, the increased oxidative stress in the kidneys of the CaMKIIα mice as shown by the increased urinary 8-hydroxydeoxyguanosine (8-OHdG) excretion and the increased expression of NAD(P)H oxidase 4 (NOX4), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (MnSOD) was decreased by Pdgfr-β gene deletion. Conclusions/interpretation The activation of PDGFR-β signalling contributes to the progress of diabetic nephropathy, with an increase in oxidative stress and mesangial expansion in CaMKIIα mice.
Establishment of a Diabetic Mouse Model with Progressive Diabetic Nephropathy
The American Journal of Pathology, 2005
Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER I␥) in pancreatic  cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER I␥ transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER I␥ transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.
Characterization of diabetic nephropathy in a transgenic model of hypoinsulinemic diabetes
AJP: Renal Physiology, 2006
Genetic mouse models provide a unique opportunity to investigate gene function in the natural course of the disease. Although diabetic nephropathy (DN) in models of type II diabetes has been well characterized, diabetic renal disease in hypoinsulinemic diabetic mice is still incompletely understood. Here, we characterized renal changes in the pdx1 PB -HNF6 transgenic mouse that exhibits β-cell dysfunction and nonobese hypoinsulinemic diabetes. Male transgenics developed hyperglycemia by the age of 7 weeks and survived over a year without insulin treatment. Diabetes ensued earlier and progressed more severely in the HNF6 males than the females. The HNF6 males exhibited albuminuria as early as 10 weeks of age and the urinary albumin excretion increased with age, exceeding 150 µg/24 h at 11 months of age. Diabetic males developed renal hypertrophy after 7 weeks of age, whereas glomerular hyperfiltration was not observed in the mice. Hypertension and hyperlipidemia were not observed in the diabetic mice. Histological analysis of the HNF6 kidneys displayed diabetic glomerular changes, including glomerular enlargement, diffuse mesangial proliferation and matrix expansion, thickened glomerular basement membrane and arteriolar hyalinosis. Mesangial matrix accumulation increased with age, resulting in nodular lesions by 44 weeks of age. Immunohistochemistry showed accumulation of type IV collagen and TGFβ1 in the mesangial area. No significant immune complex deposition was observed in the HNF6 glomeruli. Thus, the HNF6 mouse exhibits diabetic renal changes that parallel the early phase of human DN. The model should facilitate studies of genetic and environmental factors that may affect DN in hypoinsulinemic diabetes.
Activation of renal signaling pathways in db/db mice with type 2 diabetes
Kidney International, 2001
Activation of renal signaling pathways in db/db mice with type growth factors, it is now evident that metabolic and phys-2 diabetes. ical factors such as hyperglycemia, osmolality, and stretch Background. Altered regulation of signaling pathways may also activate signaling pathways and elicit phenotypic contribute to the pathogenesis of renal disease. We examined changes in target tissues [1, 2]. Elevation of ambient renal cortical signaling pathways in type 2 diabetes. plasma glucose concentration is a primary pathogenetic Methods. The status of renal cortical signaling pathways was examined in control and db/db mice with type 2 diabetes in factor in microvascular complications in both type 1 and the early phase of diabetic nephropathy associated with renal type 2 diabetes mellitus [3, 4]. The primacy of glucose matrix expansion and albuminuria. in diabetic complications has led to studies on regulation Results. Tyrosine phosphorylation of renal cortical proteins of signaling by glucose in several tissues. In the kidney, was increased in diabetic mice. Renal cortical activities of phosa major site of microvascular complications, glomerular phatidylinositol 3-kinase (PI 3-kinase) in antiphosphotyrosine immunoprecipitates, Akt (PKB), and ERK1/2-type mitogenactivity of protein kinase C (PKC) is increased in rats activated protein (MAP) kinase activities were significantly with streptozotocin-induced type 1 diabetes [5, 6]. Increaugmented sixfold (P Ͻ 0.01), twofold (P Ͻ 0.0003), and sevment in composite PKC activity involved activation of enfold (P Ͻ 0.001), respectively, in diabetic mice compared PKC [7], although an increase in activities of other with controls. A part of the increased renal cortical PI 3-kinase activity was due to insulin receptor activation, as PI 3-kinase isoenzymes of PKC is also reported [8]. Among other activity associated with  chain of the insulin receptor was signaling molecules, the activities of Erk1/2-type mitoincreased nearly fourfold (P Ͻ 0.0235). Additionally, the kinase gen-activated protein (MAP) kinase (ERK) and its upactivity of the immunoprecipitated insulin receptor  chain stream regulator, MEK, are augmented in glomeruli of was augmented in the diabetic renal cortex, and tyrosine phosrat with type 1 diabetes [9]. Increased ERK activity apphorylation of the insulin receptor was increased. In the liver, activities of PI 3-kinase in the antiphosphotyrosine immunopears to be partly due to reduction in the activity of precipitates and Akt also were increased threefold (P Ͻ 0.05) MAPK phosphatase-1 (MKP-1), and in vitro studies sugand twofold (P Ͻ 0.0002), respectively. However, there was gest that MAPK activation is PKC dependent [9, 10]. no change in the hepatic insulin receptor-associated PI 3-kinase Increased PKC activity in renal tissue has functional activity. Additionally, the hepatic ERK1/2-type MAP kinase implications as LY333531, a PKC-specific inhibitor, reactivity was inhibited by nearly 50% (P Ͻ 0.01). Conclusions. These studies demonstrate that a variety of verses the increase in both glomerular filtration rate and receptor signaling pathways are activated in the renal cortex microalbuminuria in rats with type 1 diabetes [6]. of mice with type 2 diabetes, and suggest a role for augmented Similar to type 1 diabetes, activation of glomerular insulin receptor activity in nephropathy of type 2 diabetes. PKC occurs in mice with type 2 diabetes [11]. However, the administration of LY333531 resulted in partial ame-Altered regulation of signaling pathways is gaining lioration of functional abnormalities such as albuminincreasing recognition as an important mechanism in the uria, despite the complete reversal of glomerular PKC pathogenesis of renal disease. In addition to soluble activation [11]. It is likely that in addition to PKC, other signaling pathways are also involved in pathogenesis of renal disease in type 2 diabetes. Notwithstanding the
Journal of Cellular Physiology, 2008
We have previously found progressive diabetic nephropathy in inducible cAMP early repressor (ICER Ig) transgenic (Tg) mice. The ICER Ig Tg mouse is an interesting model of sustained hyperglycemia due to its low production of insulin and insulin-producing b cells. Here in a longitudinal study we further analyzed diabetic nephropathy and structural and functional alterations in other organs, comparing our model with streptozotocin (STZ)-diabetic model mice. The high-dose STZ-diabetic model showed marked variation in blood glucose levels and severe toxicity of STZ in the liver and kidney. The low-dose STZ-diabetic model showed less toxicity, but the survival rate was very low. STZ-diabetic mice had much more variation of glomerular hypertrophy and sclerosis. Furthermore, non-specific toxicity of STZ or insulin injections to maintain optimal blood glucose levels might have another effect upon the diabetic renal changes. In contrast, ICER Ig Tg mice exhibited a stable and progressive phenotype of diabetic kidney disease solely due to chronic hyperglycemia without other modulating factors. Thus, ICER Ig Tg mouse has advantages for examining diabetic renal disease, and offers unique and very different perspectives compared to STZ model.