Ultrastructural and functional analyses of nephropathy in calmodulin‐induced diabetic transgenic mice

Carlson, Edward C.; Audette, Janice L.; Klevay, Leslie M.; Nguyen, Hugh; Epstein, Paul N.

doi:10.1002/(sici)1097-0185(199701)247:1<9::aid-ar2>3.3.co;2-q

Cited by 13 publications

(23 citation statements)

References 21 publications

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“…In summary, it is difficult to reconcile our GBM thickness data with numerous morphometric studies, including our own (Carlson et al, 1997(Carlson et al, , 2003, that indicate increased microvascular basement membrane thickness is a concomitant of hyperglycemia. It is also difficult to escape the conclusion that high blood glucose may be sufficient but not required for excessive GBM thickening to occur.…”

Section: Gbm Morphometry Morphometric Analyses Of Allcontrasting

confidence: 55%

“…PEI is a cationic molecule that can be made electron-dense by the addition of 2% phosphotungstic acid; it binds to AS and is readily imaged by TEM. Aliquot 2 samples were subjected to sequential detergent extraction (Carlson et al, 1978) and subsequently were fixed and postfixed for TEM or scanning electron microscopy (SEM) as described previously (Carlson et al, 1997). Thick sections were stained with toluidine blue (1% in 1% sodium borate) and observed by bright-field microscopy.…”

Section: Microscopymentioning

confidence: 99%

“…Fixed tissues to be examined by SEM were immersed in liquid N 2 -cooled Freon 22, cleaved with a liquid N 2 -cooled razor blade, and prepared as previously described (Carlson et al, 1997). Cleaved tissue samples were mounted on aluminum specimen stubs with colloidal silver and coated with a layer of gold-palladium in a Denton Desk II sputter coater.…”

Section: Microscopymentioning

confidence: 99%

“…We have previously shown in several species that at the level of LM, detergent treatment completely removed cellular components while glomerular ECM components, including various renal basement membranes, maintain their normal histoarchitectures Hinds, 1981, 1983;Carlson and Kenney, 1982;Carlson and Chatterjee, 1983;Carlson and Surerus, 1986;Marion and Carlson, 1989;Carlson et al, 1997). Likewise in the current study, whole acellular glomeruli from BB/DR, BB/DP h , and BB/ DP n animals at 1 year postonset of diabetes showed normal morphological features and were virtually indistinguishable with only minor increases in MM in BB/DP h kidneys.…”

Section: Light Microscopic Studiesmentioning

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 Allcontrasting

confidence: 55%

Section: Microscopymentioning

confidence: 99%

Section: Microscopymentioning

confidence: 99%

Section: Light Microscopic Studiesmentioning

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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“…We used the OVE26 transgenic mouse which develops early-onset type I diabetes. This mouse model displays characteristics of early and late-stage diabetic nephropathy in humans, including initial increase followed by decline in glomerular filtration rate, renal hypertrophy, mesangial expansion, and thickening of glomerular basement membrane, and they develop severe proteinuria, as well as tubulointerstitial fibrosis (Carlson et al 1997;Powell et al 2009;Zheng et al 2004). To better correlate this stress response to characteristics associated with the pathogenesis of DN, diabetic OVE26 mice with mild to severe albuminuria were used.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of endoplasmic reticulum stress-response proteins in different renal tubule subtypes of OVE26 diabetic mice

Barati

Powell

Kechavarzi

et al. 2016

Cell Stress and Chaperones

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Regulation of the endoplasmic reticulum (ER) stress-response pathway during the course of diabetes specifically in renal tubules is unclear. Since tubule cell dysfunction is critical to progression of diabetic nephropathy, this study analyzed markers of ER stress response and ER chaperones at different stages of diabetes and in different renal tubule subtypes of OVE26 type-1 diabetic mice. ER stress-responseinduced chaperones GRP78, GRP94, and protein disulfide isomerase (PDI) were increased in isolated cortical tubules of older diabetic mice, while PDI was decreased in tubules of young diabetic mice. Immunofluorescence staining of kidneys from older mice showed GRP78 and PDI upregulation in all cortical tubule segments, with substantial induction of PDI in distal tubules. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) phosphorylation was increased in cortical tubules of young diabetic mice, with no differences between older diabetic and control mice. Expression of ER stress-induced PERK inhibitor p58 IPK was decreased and then increased in all tubule subtypes of young and older mice, respectively. Knockdown of PERK by small interfering RNA (siRNA) increased fibronectin secretion in cultured proximal tubule cells. Tubules of older diabetic mice had significantly more apoptotic cells, and ER stress-induced proapoptotic transcription factor C/EBP homologous protein (CHOP) was increased in proximal and distal tubules of diabetic mice and diabetic humans. CHOP induction in OVE26 mice was not altered by severity of proteinuria. Overexpression of CHOP in cultured proximal tubule cells increased expression of fibronectin. These findings demonstrate differential ER stress-response signaling in tubule subtypes of diabetic mice and implicate a role for PERK and CHOP in tubule cell matrix protein production.

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Podocyte‐specific overexpression of metallothionein mitigates diabetic complications in the glomerular filtration barrier and glomerular histoarchitecture: a transmission electron microscopy stereometric analysis

Carlson

Chhoun

Laturnus

et al. 2013

Diabetes Metabolism Res

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Ultrastructural and functional analyses of nephropathy in calmodulin‐induced diabetic transgenic mice

Cited by 13 publications

References 21 publications

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

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

Differential expression of endoplasmic reticulum stress-response proteins in different renal tubule subtypes of OVE26 diabetic mice

Podocyte‐specific overexpression of metallothionein mitigates diabetic complications in the glomerular filtration barrier and glomerular histoarchitecture: a transmission electron microscopy stereometric analysis

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