Resistance to glomerular injury in the diabetic biobreeding rat

Lg, Feld; Cachero, S; En, Ellis; Dedeoglu, Ozen; Ueda, Yoshimichi; Leonard, Charles E.; Letizia, R; Mallon, V; Liew, JB Van

doi:10.1113/expphysiol.1995.sp003910

Cited by 14 publications

(13 citation statements)

References 20 publications

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“…animal types showed substantial increases in GBM thickness with age, and these data were consistent with several studies that indicated this parameter was a reliable biomarker of aging in rats (Yagahashi et al, 1978;Cohen et al, 1987;Feld et al, 1995). Our morphometric data also showed that GBMs in BB/DP h animals were significantly thicker than age-matched BB/DR controls at 3 months, 6 months, and 1 year postonset of hyperglycemia.…”

Section: Gbm Morphometry Morphometric Analyses Of Allsupporting

confidence: 91%

“…Our morphometric data also showed that GBMs in BB/DP h animals were significantly thicker than age-matched BB/DR controls at 3 months, 6 months, and 1 year postonset of hyperglycemia. This was also not unexpected as other investigators showed that as early as 6 months postonset of hyperglycemia, GBMs in BB/DP rats were thicker than age-matched BB/DR rats (Brown et al, 1983;Cohen et al, 1987;Chakrabarti and Sima, 1989;Feld et al, 1995). Also, Feld et al (1995) showed that at 1 year, GBMs were 25% wider in BB/DP rats than in age-matched BB/DR controls.…”

Section: Gbm Morphometry Morphometric Analyses Of Allsupporting

confidence: 59%

“…This was not unexpected, as data from other studies (Cohen et al, 1987;Feld et al, 1995) indicated that moderately hyperglycemic BB rats achieved lower body weights than normoglycemic controls. Although the precise reasons for body weight reduction in diabetics are not fully understood, overall BB/DP h , and (C) BB/DP n rats showing similar glomerular size and distribution of glomerular basement membranes.…”

Section: Body Weightssupporting

confidence: 59%

“…Accordingly, reduction of AS density in GBMs is widely regarded as contributory to diabetic proteinuria. However, since only modest levels of urine protein have been reported for moderately hyperglycemic BB rats (Cohen et al, 1987;Velasquez et al, 1990;Zamlauski-Tucker et al, 1992;Feld et al, 1995), it seems possible that maintenance of normal complements of AS as shown in the current investigation may be related functionally to known relatively low levels of proteinuria in diabetic BB rats.…”

Section: Electron Microscopic Studiesmentioning

confidence: 65%

“…Previous morphological analyses in the BB rat show significant renal alterations in hyperglycemic (BB/DP h ) rats over age-matched BB/DR animals, including increased thickness in glomerular basement membrane (GBM) (Cohen et al, 1987;Chakrabarti and Sima, 1991;Feld et al, 1995), increases in mesangial volume (Cohen et al, 1987;Chakrabarti and Sima, 1991), and a loss of GBM anionic sites (AS) (Chakrabarti and Sima, 1991). Nevertheless, important information is not available regarding the correlation of nephropathic changes in the extracellular matrix (ECM) associated with the hyperglycemia of diabetes.…”

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confidence: 99%

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Significant glomerular basement membrane thickening in hyperglycemic and normoglycemic diabetic‐prone BB Wistar rats

et al. 2004

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The diabetic-prone BioBreeding Wistar rat (BB/DP) is an autoimmune model of insulindependent diabetes mellitus. Approximately 80 -90% of the animals are hyperglycemic (BB/ DP h ) by 90 -120 days of age while those that do not become diabetic in adolescence (BB/DP n ) remain normoglycemic for life. Likewise, rats in the diabetes-resistant (BB/DR) strain are normoglycemic. Although renal morphological studies have been carried out in this model, ultrastructural observations of age-and diabetes-related extracellular matrix (ECM) changes, including glomerular basement membrane (GBM) morphometry, are not available. Moreover, possible renal changes in the relatively uncommon BB/DP n control animals have not been reported. The current electron microscopic study was carried out to investigate temporal changes in detergent-treated acellular ECM in BB/DP h rats at 2 weeks, 3 months, 6 months, and 1 year postonset of moderate hyperglycemia. Age-matched BB/DR and BB/DP n control animals were also examined. Our data demonstrate age-and diabetes-related alterations in mesangial matrix distributions and GBM widths and show for the first time significant increases in GBM thickening in both hyperglycemic (BB/DP h ) and normoglycemic (BB/DP n ) rats when compared to age-matched BB/DR controls. Surprisingly, the rate of increase is greatest in BB/DP n animals. Although the pathogenesis of diabetic basement membrane disease is not completely understood, GBM thickening is widely regarded as a morphological consequence of hyperglycemia. However, data in the current investigation show that ECM alterations, including significantly increased GBM thickness, may occur in genetically diabetic animals in the absence of hyperglycemia. © 2004 Wiley-Liss, Inc. Key words: diabetes; glomerular basement membrane thickness; BB Wistar ratsThe BioBreeding Wistar rat (BB rat) is an autoimmune model of insulin-dependent diabetes mellitus (IDDM) discovered in 1974 in a colony of pathogen-free Wistar rats (Chappel and Chappel, 1983). Like human IDDM, the onset of clinical symptoms in diabetes-prone (BB/DP) BB rats appear during adolescence, generally between 60 and 120 days of age (Butler et al., 1983;Chappel and Chappel, 1983). These are characterized by rapid weight loss, polyuria, polydipsia, ketonuria, and finally death unless exogenous insulin is administered (Chappel and Chappel, 1983;Like and Rossini, 1984). The incidence of diabetes through 120 days of age is 60 -90% in most colonies and averaged 86% in a viral antibody-free NIH colony in Worcester, Massachusetts (Crisa et al., 1992). The diabetes exhibited by BB rats is not attributed to a single dominant or recessive gene, but the etiology seems to include a genetic component (Chappel and Chappel, 1983).

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Section: Gbm Morphometry Morphometric Analyses Of Allsupporting

confidence: 91%

Section: Gbm Morphometry Morphometric Analyses Of Allsupporting

confidence: 59%

Section: Body Weightssupporting

confidence: 59%

Section: Electron Microscopic Studiesmentioning

confidence: 65%

mentioning

confidence: 99%

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Significant glomerular basement membrane thickening in hyperglycemic and normoglycemic diabetic‐prone BB Wistar rats

et al. 2004

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Ultrastructural morphometry of capillary basement membrane thickness in normal and transgenic diabetic mice

et al. 2003

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Capillary basement membrane (CBM) thickening is an ultrastructural hallmark in diabetic patients and in animal models of diabetes. However, the wide variety of tissues sampled and diverse methods employed have made the interpretation of thickness data difficult. We showed previously that acellular glomerular BMs in OVE26 transgenic diabetic mice were thickened beyond normal age-related thickening, and in the current study we hypothesized that other microvascular BMs likewise would show increased widths relative to age-matched controls. Accordingly, a series of tissues, including skeletal and cardiac muscle, ocular retina and choriod, peripheral nerve, lung, pancreas, and renal glomerulus was collected from 300 -350-day-old normal and transgenic mice. Transmission electron micrographs of cross sections through capillary walls were prepared, and CBM thickness (CBMT) was determined by the "orthogonal intercept" method. Morphometric analyses showed highly variable transgene-related BMT increases in the sampled tissues, with glomerular BM showing by far the greatest increase (ϩ87%). Significant thickness increases were also seen in the retina, pulmonary alveolus, and thoracoabdominal diaphragm. BMT increases were not universal; however, most were modestly widened, and those that were thickest in controls generally showed the greatest increase. Although the pathogenesis of diabetes-related increases in CBM is poorly understood, data in the current study showed that in OVE26 transgenic mice increased BMT was a frequent concomitant of hyperglycemia. Accordingly, it seems likely that hyperglycemia-induced microvascular damage may be a contributing factor in diabetic BM disease, and that microvessel cellular and extracellular heterogeneity may limit the extent of CBM thickening in diverse tissues. Anat Rec Part A 271A: 332-341, 2003. © 2003 Key words: diabetes; basement membrane thickness; electron microscopy; transgenic diabetic mice OVE26 transgenic mice are diabetic as a result of the specific overexpression of calmodulin in pancreatic beta cells (Epstein et al., 1989(Epstein et al., , 1992. Histological studies show that this results in beta cell destruction early in life, and by 30 -55 days of age glucose values exceed 450 mg/dl. At the same time, insulin levels are reduced to 42% of control levels. OVE26 mice are a particularly valuable model of diabetes, because beta cell toxins need not be administered to induce the disease, and the animals can survive well over a year without exogenous insulin administration (probably because of a small amount of residual insulin secretion). Moreover, because both males and females are fertile for several months without insulin therapy, the transgenic line has been maintained continuously for more than 14 years.Several studies have shown that the OVE26 diabetic model is useful for examining chronic complications of diabetes. This was particularly evident in a previous study of the kidney (Carlson et al., 1997) in which transmission electron microscopy (TEM) morphometry sh...

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