Prevention of Diabetic Nephropathy by Diet Control in the <i>db/db</i> Mouse

Lee, Stanley M.; Bressler, Rubin

doi:10.2337/diab.30.2.106

Cited by 133 publications

(43 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After 10–20 weeks of sustained hyperglycemia, it exhibits significant renal pathology including glomerular mesangial expansion, accumulation of mesangial matrix encroaching the normal capillary network, overexpression of mRNAs encoding alpha 1 (IV) collagen and fibronectin, reduction in creatinine clearance, and a rise in serum creatinine concentration [6, 7, 8, 9, 10, 11]. These renal structural and functional abnormalities resemble, in their evolution and nature, those observed in human diabetes, rendering the db/db mouse a potentially useful model for study of pathogenetic influences and intervention strategies in the nephropathy of type II diabetes [7, 8, 9, 11, 12, 13]. We have used the db/db mouse to show that increased circulating concentrations of glycated albumin play a major causative role in the genesis of diabetic kidney disease by demonstrating that the renal cell biology, histomorphometric and functional abnormalities observed in these animals are prevented when the influence of excess plasma glycated albumin is blocked by treatment with monoclonal antibodies that specifically react with albumin modified by Amadori glucose adducts [7, 8, 9, 14].…”

Section: Introductionmentioning

confidence: 99%

The Renal TGF-β System in the db/db Mouse Model of Diabetic Nephropathy

Cohen

Sharma

Guo

et al. 1998

Nephron Exp Nephrol

View full text Add to dashboard Cite

The prosclerotic cytokine transforming growth factor beta 1 (TGF-β₁) has been causally implicated in renal pathobiology in diabetes. We sought evidence that the TGF-β system participates in the nephropathic process in the db/db mouse, a hyperinsulinemic model of genetic diabetes that develops abnormalities in renal morphology and function that parallel those in human diabetic nephropathy. In support of this hypothesis, we found that steady state levels of mRNA encoding the TGF-β type II receptor were significantly increased in renal cortex from db/db diabetic mice. Additionally, the translated TGF-β type II receptor protein, assessed by immunoblot, also was increased in diabetic kidneys. However, in contrast to rodents with insulin-deficient diabetes, steady state levels of mRNA encoding TGF-β₁ in the renal cortex of diabetic db/db mice did not differ from those in cortex from nondiabetic (db/m) littermate controls. Further, concentrations of TGF-β protein, measured by immunoassay and bioassay, were significantly lower in extracts prepared from renal cortex of diabetic animals compared with those from nondiabetic controls. Urine and serum concentrations of immunoreactive TGF-β₁ also were reduced in diabetic mice. The findings are consistent with upregulation of TGF-β type II receptor activity as a consequence of hyperglycemia in the hyperinsulinemic db/db mouse and suggest that hyperinsulinemia inhibits TGF-β₁ production. The results further suggest that type II receptor upregulation is a contributing factor to the increased gene expression of renal cortical mRNAs encoding the extracellular matrix proteins fibronectin and alpha 1 (IV) collagen and to the renal abnormalities observed in this animal model.

show abstract

Section: Introductionmentioning

confidence: 99%

The Renal TGF-β System in the db/db Mouse Model of Diabetic Nephropathy

Cohen

Sharma

Guo

et al. 1998

Nephron Exp Nephrol

View full text Add to dashboard Cite

show abstract

“…The initial detailed studies by Like et al [27] over 30 years ago, followed by studies by Lee and Bressler [22] 10 years later, demonstrated that before the onset of hyperglycemia in these diabetic mice there was no difference in various glomerular parameters when compared with their nondiabetic littermates. After 5 to 6 months of age, diabetic mice have larger glomeruli and an increase in mesangial matrix when assessed by light microscopy.…”

Section: Glomerular Changes In the Db/db Mousementioning

confidence: 98%

“…Natural history of diabetes and obesity in the db/db mouse All db/db mice are obese after the age of 4 weeks [22]. Hyperinsulinemia can be seen after 10 days of age, with a 50% rise in body weight noted after 2 months of age.…”

Section: C57blks/j Versus C57bl/6j Background In the Db/db Mousementioning

confidence: 98%

See 1 more Smart Citation

Use of genetic mouse models in the study of diabetic nephropathy

Allen¹,

Cooper²,

Lan

2004

Curr Diab Rep

View full text Add to dashboard Cite

The study of experimental diabetic nephropathy in rodent models has led to many changes in the clinical management of human diabetic nephropathy. With the development of technology to generate knockout and transgenic animals, the mouse has become a favored species in medical research. There are several genetic mouse models of diabetes, with the majority being models of type 2 diabetes mellitus. These include the hypoinsulinemic nonobese diabetic mouse, the KKAy mouse, the New Zealand obese mouse, the hyperinsulinemic ob/ob mouse, and the different strains of obese hyperinsulinemic db/db mouse. Each of these models displays some renal changes, but by far the best model of renal disease and the one that is the most studied is the db/db mouse. The db/db mouse displays substantial glomerular pathology, including mesangial matrix expansion and modest albuminuria. It has been reported that the db/db mouse has a decline in creatinine clearance after 5 months of age, but more specific approaches are warranted to confirm these findings. A number of intervention studies show renoprotection in this model. Although mice have many advantages, such as being able to be crossbred with genetically manipulated animals, in many ways they are not very similar to humans, and in some respects the rat may be a better choice, particularly in relation to some features of end-organ injury.

show abstract

“…We have identified a heteroaryl acid, designated EXO-226, that binds to glycatable lysine residues in albumin and thereby impedes the condensation of free glucose with ε-amino groups in the protein, and that reduces glycated albumin concentrations in human subjects [23, 24]. On the basis of these findings, we evaluated whether a treatment regimen of EXO-226 that significantly lowers plasma glycated albumin concentrations can beneficially influence abnormalities in renal structure and function that are known to occur in the db/db mouse model of type 2 diabetes [7, 8, 9, 25, 26, 27]. …”

Section: Introductionmentioning

confidence: 99%

Inhibiting Albumin Glycation Ameliorates Diabetic Nephropathy in the <i>db/db</i> Mouse

Cohen¹,

Masson²,

Hud³

et al. 2000

Nephron Exp Nephrol

View full text Add to dashboard Cite

Albumin modified by Amadori glucose adducts stimulates the expression of extracellular matrix proteins by glomerular mesangial and endothelial cells, and has been mechanistically linked to the pathogenesis of diabetic nephropathy. To test the hypothesis that inhibiting the formation of glycated albumin might beneficially influence the development of kidney disease in diabetes, we treated diabetic db/db mice for 12 weeks with a low-molecular-weight compound (EXO-226) that impedes the condensation of free glucose with lysine ε-amino groups in albumin. Administration of EXO-226 (3 mg/kg) twice daily by gavage normalized the plasma concentration of glycated albumin within days after initiation of treatment and maintained glycated albumin within the normal range throughout the study, despite persistent and severe hyperglycemia. Urine albumin excretion, which was markedly increased at the start of the study (age 12 weeks), was significantly reduced in treated diabetic animals compared with their untreated diabetic littermates. The fall in creatinine clearance that was observed in untreated diabetic animals was prevented in diabetic littermates that received treatment. Compared with the nondiabetic controls, the amount of glomerular mesangial matrix was threefold greater in untreated diabetic mice; in contrast, the mesangial matrix fraction was only 1.5 times that of nondiabetic controls in the treated diabetic animals, representing a reduction in mesangial matrix accumulation of more than 50%. EXO-226 also reduced the overexpression of mRNA encoding for α1 (IV) collagen in renal cortex of db/db mice. We conclude that normalization of plasma glycated albumin concentrations with the glycation inhibitor EXO-226 ameliorates the glomerular structural and functional abnormalities associated with diabetic nephropathy in the db/db mouse.

show abstract

Prevention of Diabetic Nephropathy by Diet Control in the db/db Mouse

Cited by 133 publications

References 0 publications

The Renal TGF-β System in the db/db Mouse Model of Diabetic Nephropathy

The Renal TGF-β System in the db/db Mouse Model of Diabetic Nephropathy

Use of genetic mouse models in the study of diabetic nephropathy

Inhibiting Albumin Glycation Ameliorates Diabetic Nephropathy in the <i>db/db</i> Mouse

Contact Info

Product

Resources

About