Renal Lesions in Spontaneous Insulin-dependent Diabetes Mellitus in the Nonobese Diabetic Mouse: Acute Phase of Diabetes

Maeda, Michiharu; Yabuki, Akira; Suzuki, Syusaku; Matsumoto, Mitsuharu; Taniguchi, Kazuyuki; Nishinakagawa, Hayao

doi:10.1354/vp.40-2-187

Cited by 35 publications

(34 citation statements)

References 38 publications

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“…when there was significant albuminuria. In the NOD mouse, which is an established model of spontaneous insulin-dependent diabetes mellitus [34,35], morphological changes and temporary hyperfiltration at D10 [36,37] preceded the albuminuria that, in our hands, was apparent after 27 weeks. In humans, diabetic nephropathy is a late complication occurring progressively in susceptible patients after 15-30 years of diabetes, which probably corresponds to 25-30 weeks in mice when considering their shorter lifespan.…”

Section: Discussionmentioning

confidence: 51%

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

et al. 2006

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Aims/hypothesis Despite the fact that diabetic nephropathy is an increasingly common disorder that may lead to uraemia, the underlying mechanisms are still poorly understood and there is no specific therapy. To clarify whether long-term diabetes alters glomerular size-or charge-selectivity or both, we studied non-obese diabetic mice for up to 40 weeks. Materials and methods During the study period, spot urine was collected and blood pressure measured. At weeks 10 and 40, the right kidney was isolated and perfused at 8°C to inhibit tubular function, allowing for analysis of glomerular selectivity with albumin and Ficoll clearance. The left kidney was removed for further investigation using electron microscopy and molecular biology. Real-time PCR with low-density arrays was done to evaluate renal cortex mRNA expression of proteoglycans and other components in the glomerular barrier. After 40 weeks of diabetes, kidneys showed morphological changes typical of diabetic complications. Results At 40 weeks, the fractional clearance for negatively charged albumin was three times higher in the diabetic animals (0.0160) than in controls (0.0051, p<0.001), while fractional clearance for neutral Ficoll 35.5 Å with a Stokes Einstein radius similar to that of albumin was unaffected. In addition, protein and mRNA levels for versican and decorin were downregulated after 40 weeks of diabetes. Conclusions/interpretation We conclude that glomerular charge-but not size-selectivity was impaired in the diabetic animals with proteinuria. Also, glomerular components such as versican, decorin and fibromodulin were found to be downregulated after 40 weeks of diabetes.

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Section: Discussionmentioning

confidence: 51%

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

et al. 2006

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“…Cell proliferation is used as an early indicator of cell stress/damage in the kidney and occurs in the renal glomeruli and tubules in diabetic mice (14,24,38). PCNA is a DNA polymerase-associated protein expressed in proliferating cells (39).…”

Section: Initiation Of Menopausementioning

confidence: 99%

Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause

Keck¹,

Romero-Aleshire²,

Cai³

et al. 2007

American Journal of Physiology-Renal Physiology

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Changes in the estrogen/testosterone balance at menopause may negatively influence the development of diabetic kidney disease. Furthermore, recent studies suggest that changes in hormone levels during perimenopause may influence disease development. Injection of 4-vinylcyclohexene diepoxide (VCD) in B 6C3F1 mice induces gradual ovarian failure, preserving both the perimenopausal (peri-ovarian failure) and menopausal (post-ovarian failure) periods. To address the impact of the transition into menopause on the development of diabetes and diabetic kidney damage, we used streptozotocin (STZ)-induced diabetes in the VCD model of menopause. After 6 wk of STZ-induced diabetes, blood glucose was significantly increased in post-ovarian failure (post-OF) diabetic mice compared with cycling diabetic mice. In peri-ovarian failure (peri-OF) diabetic mice, blood glucose levels trended higher but were not significantly different from cycling diabetic mice, suggesting a continuum of worsening blood glucose across the menopausal transition. Cell proliferation, an early marker of damage in the kidney, was increased in post-OF diabetic mice compared with cycling diabetic mice, as measured by PCNA immunohistochemistry. In post-OF diabetic mice, mRNA abundance of early growth response-1 (Egr-1), collagen-4␣1, and matrix metalloproteinase-9 were increased and 3␤-hydroxysteroid dehydrogenase 4 (3␤-HSD4) and transforming growth factor-␤2 (TGF-␤2) were decreased compared with cycling diabetic mice. In peri-OF diabetic mice, mRNA abundance of Egr-1 and 3␤-HSD4 were increased, and TGF-␤2 was decreased compared with cycling diabetic mice. This study highlights the importance and utility of the VCD model of menopause, as it provides a physiologically relevant system for determining the impact of the menopausal transition on diabetes and diabetic kidney damage. diabetes; 3␤-HSD4; perimenopause; real-time PCR; estrogen DIABETES IS ONE OF THE MOST prevalent and costly diseases afflicting developed countries, with estimates placing the current global cost of diabetes at $150 billion a year (1). Approximately one-third of all diabetics die of end-stage renal disease (33) due to progressive renal damage and hypertension.17␤-Estradiol is considered protective against the development and progression of many diseases, including cardiovascular (9) and renal disease (34). Premenopausal women have slower rates of progression of nondiabetic renal disease than age-matched men (23), a difference that seems to disappear after menopause (3). The impact of estrogen on diabetic renal disease is less clear, however. Several studies demonstrate a decreased incidence of diabetic renal disease in women, but others have found no difference between men and women (34).The 5-10 years preceding menopause is termed perimenopause, and during this time estrogen levels fluctuate, with periods of low estrogen interspersed with periods of very high estrogen (31). The periods of low estrogen become more frequent as a woman approaches menopause until circulating levels of 17␤...

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“…Maeda et al (47) reported renal hypertrophy, glomerular injury and structural alteration of the proximal straight tubules during the acute phase of diabetes in nonobese diabetic mice. The renal lesions in type-2 diabetic patients may be caused by cardiovascular diseases such as arteriosclerosis and hypertension (48).…”

Section: Onset Of Diabetic Nephropathymentioning

confidence: 99%

The use of lysosomal enzymuria in the early detection and monitoring of the progression of diabetic nephropathy

Gatsing

Garba

Adoga

2006

Indian J Clin Biochem

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Renal Lesions in Spontaneous Insulin-dependent Diabetes Mellitus in the Nonobese Diabetic Mouse: Acute Phase of Diabetes

Cited by 35 publications

References 38 publications

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause

The use of lysosomal enzymuria in the early detection and monitoring of the progression of diabetic nephropathy

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