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  • 1
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    Online Resource
    Podocyte Detachment and Reduced Glomerular Capillary Endothelial Fenestration in Human Type 1 Diabetic Nephropathy
    American Diabetes Association ; 2007
    In:  Diabetes Vol. 56, No. 8 ( 2007-08-01), p. 2155-2160
    Details
    In: Diabetes, American Diabetes Association, Vol. 56, No. 8 ( 2007-08-01), p. 2155-2160
    Abstract: The aim of this study was to investigate the structural characteristics of podocytes and endothelial cells in diabetic nephropathy. We studied 18 patients with type 1 diabetes (seven normoalbuminuric, six microalbuminuric, and five proteinuric), and six normal control subjects. Groups were not different for age. Type 1 diabetic groups were not different for diabetes duration or age at diabetes onset. Podocyte foot process width (FPW), fraction of glomerular basement membrane (GBM) surface with intact nondetached foot processes (IFP), fraction of glomerular capillary luminal surface covered by fenestrated endothelium [SS(Fenestrated/cap)] and classic diabetic glomerulopathy lesions were morphometrically measured. Albumin excretion (AER) and glomerular filtration (GFR) rates were also measured. GFR correlated inversely and AER directly with GBM and mesangial measurements in diabetic patients. FPW correlated inversely with GFR (r = −0.71, P = 0.001) and directly with AER (r = 0.66, P = 0.003), GBM, and mesangial parameters. The GBM fraction covered by IFP was decreased in proteinuric versus control subjects (P = 0.001), normoalbuminuric patients (P = 0.0002) and microalbuminuric patients (P = 0.04) and correlated with renal structural and functional parameters, including AER (r = −0.52, P = 0.03). Only 78% of GBM was covered by IFP in proteinuric patients. SS(Fenestrated/cap) was reduced in normoalbuminuric (P = 0.03), microalbuminuric (P = 0.03), and proteinuric (P = 0.002) patients versus control subjects. SS(Fenestrated/cap) correlated with mesangial fractional volume per glomerulus (r = −0.57, P = 0.01), IFP (r = 0.61, P = 0.007), and FPW (r = −0.58, P = 0.01). These novel studies document that podocyte detachment and diminished endothelial cell fenestration are related to classical diabetic nephropathy lesions and renal function in type 1 diabetic patients and support a need for further studies of podocyte/GBM adherence and podocyte/endothelial cell functional interactions in diabetic nephropathy.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db07-0019
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2007
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  • 2
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    Diabetic Nephropathy Is Associated With Gene Expression Levels of Oxidative Phosphorylation and Related Pathways
    American Diabetes Association ; 2006
    In:  Diabetes Vol. 55, No. 6 ( 2006-06-01), p. 1826-1831
    Details
    In: Diabetes, American Diabetes Association, Vol. 55, No. 6 ( 2006-06-01), p. 1826-1831
    Abstract: The in vitro behavior of skin fibroblasts from patients with or without diabetic nephropathy is associated with diabetic nephropathy risk. Here we compared skin fibroblast gene expression profiles from two groups of type 1 diabetic patients: 20 with very fast (“fast-track”) versus 20 with very slow (“slow-track”) rates of development of diabetic nephropathy lesions. Gene expression profiles of skin fibroblasts grown in 25 mmol/l glucose for 36 h were assessed by Affymetrix HG-U133A GeneChips to determine the proportion of genes in a given biological pathway that were directionally consistent in their group differences. Five pathways reached statistical significance. All had significantly greater proportions of genes with higher expression levels in the fast-track group. These pathways, the first four of which are closely related and have overlapping genes, included oxidative phosphorylation (P & lt; 0.001), electron transport system complex III (P = 0.017), citrate cycle (P = 0.037), propanoate metabolism (P = 0.044), and transcription factors (P = 0.046). These results support the concept that oxidative phosphorylation and related upstream pathways may be important in the pathogenesis of diabetic nephropathy. Whether these findings reflect inherent genetic cellular characteristics, “cell memory,” or both requires further study.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db05-1438
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2006
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  • 3
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    Cellular Basis of Diabetic Nephropathy
    American Diabetes Association ; 2002
    In:  Diabetes Vol. 51, No. 12 ( 2002-12-01), p. 3577-3581
    Details
    In: Diabetes, American Diabetes Association, Vol. 51, No. 12 ( 2002-12-01), p. 3577-3581
    Abstract: Transforming growth factor-β (TGF-β) may be critical in the development of diabetic nephropathy (DN), and genetic predisposition is an important determinant of DN risk. We evaluated mRNA expression levels of TGF-β system components in cultured skin fibroblasts (SFs) from type 1 diabetic patients with fast versus slow development of DN. A total of 125 long-standing type 1 diabetic patients were ranked by renal mesangial expansion score (MES) based on renal biopsy findings and diabetes duration. Patients in the highest quintile of MES who were also microalbuminuric or proteinuric (n = 16) were classified as “fast-track” for DN, while those in the lowest quintile who were also normoalbuminuric (n = 23) were classsified as “slow-track” for DN. Twenty-five normal subjects served as control subjects. SFs were cultured in medium with 25 mmol/l glucose for 36 h. SF mRNA expression levels for TGF-β1, TGF-β type II receptor (TGF-β RII), thrombospondin-1, and latent TGF-β binding protein-1 (LTBP-1) were measured by real-time RT-PCR. LTBP-1 mRNA expression was reduced in slow-track (0.99 ± 0.38) versus fast-track patients (1.65 ± 0.52, P = 0.001) and control subjects (1.41 ± 0.7, P = 0.025). mRNA levels for TGF-β1, TGF-β RII, and thrombospondin-1 were similar in the three groups. Reduced LTBP-1 mRNA expression in SFs from slow-track patients may reflect genetically determined DN protection and suggests that LTBP-1 may be involved in the pathogenesis of DN through the regulation of TGF-β activity.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.51.12.3577
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2002
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  • 4
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    Online Resource
    Cellular Basis of Diabetic Nephropathy
    American Diabetes Association ; 2002
    In:  Diabetes Vol. 51, No. 2 ( 2002-02-01), p. 506-513
    Details
    In: Diabetes, American Diabetes Association, Vol. 51, No. 2 ( 2002-02-01), p. 506-513
    Abstract: This study was designed to elucidate the cellular basis of risk of or protection from nephropathy in patients with type 1 diabetes. Entry criteria included diabetes duration of ≥8 years (mean duration, 22.5 years) and glomerular filtration rate (GFR) & gt;30 ml·min−1·1.73 m−2. Patients were classified, on the basis of the estimated rate of mesangial expansion, as “fast-track” (upper quintile) or “slow-track” (lower quintile). A total of 88 patients were normoalbuminuric, 17 were microalbuminuric, and 19 were proteinuric. All three groups had increased glomerular basement membrane (GBM) width and mesangial fractional volume [Vv(Mes/glom)], with increasing severity from normoalbuminuria to microalbuminuria to proteinuria but with considerable overlap among groups. Vv(Mes/glom) (r = 0.75, P & lt; 0.001) and GBM width (r = 0.63, P & lt; 0.001) correlated with albumin excretion rate (AER), whereas surface density of peripheral GBM per glomerulus [Sv(PGBM/glom)] (r = 0.50, P & lt; 0.001) and Vv(Mes/glom) (r = −0.48, P & lt; 0.001) correlated with GFR. Vv(Mes/glom) and GBM width together explained 59% of AER variability. GFR was predicted by Sv(PGBM/glom), AER, and sex. Fast-track patients had worse glycemic control, higher AER, lower GFR, more hypertension and retinopathy, and, as expected, worse glomerular lesions than slow-track patients. Thus, there are strong relationships between glomerular structure and renal function across the spectrum of AER, but there is considerable structural overlap among AER categories. Given that normoalbuminuric patients may have advanced glomerulopathy, the selection of slow-track patients based on glomerular structure may better identify protected patients than AER alone.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.51.2.506
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2002
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  • 5
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    Effect of Cyclosporin on Generalized Shwartzman Reaction in Diabetic Rats
    American Diabetes Association ; 1990
    In:  Diabetes Vol. 39, No. 1 ( 1990-01-01), p. 83-86
    Details
    In: Diabetes, American Diabetes Association, Vol. 39, No. 1 ( 1990-01-01), p. 83-86
    Abstract: The effect of cyclosporin (CsA) on the endotoxin-induced generalized Shwartzman reaction (GSR) was studied in diabetic and nondiabetic rats. After 4.5 wk of diabetes, CsA (20 mg/kg) or intralipid as a control substance was given intraperitoneally daily for 10 days. Next, diabetic rats were given either high-dose (2 mg/kg) or low-dose (0.1 mg/kg) endotoxin (Escherichia coli 026 :B6 lipopolysaccharide B) as a single injection. The rats were killed at intervals of 1, 4, 8, and 24 h. No significant glomerular thrombi were seen in the nondiabetic control animals, whereas the severity of glomerular thrombi in the diabetic animals was dependent on the presence or absence of CsA, endotoxin dose, and degree of glycemic control. In the diabetic rats, glomerular thrombi occurred maximally at 4 h but were no longer present at 24 h. The CsA/high-dose–endotoxin rats had fewer glomerular thrombi than rats receiving the intralipid/high–dose endotoxin, but this difference was not statistically significant. The CsA/low-dose–endotoxin rats had increased glomerular thrombi compared with the intralipid/low-dose–endotoxin rats (P & lt; 0.01). Insulin treatment reduced the glomerular capillary thrombi in the CsA/low-dose–endotoxin diabetic animals. Thus, CsA aggravates the GSR with low-dose endotoxin but has no significant effect when high-dose endotoxin is given. Improved glycemic control reduces the GSR in CsA-treated rats. Thus, the interrelationships of diabetes, endotoxin, and CsA on the GSR are complex, and the pathogenesis of these events is unclear.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diacare.39.1.83
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1990
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  • 6
    Online Resource
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    Effects of IGF-I and Glucose on Protein and Proteoglycan Synthesis by Human Fetal Mesangial Cells in Culture
    American Diabetes Association ; 1991
    In:  Diabetes Vol. 40, No. 10 ( 1991-10-01), p. 1346-1354
    Details
    In: Diabetes, American Diabetes Association, Vol. 40, No. 10 ( 1991-10-01), p. 1346-1354
    Abstract: Abnormalities in proteoglycan metabolism have been implicated in the pathogenesis of diabetic nephropathy. Whether hyperglycemia plays a direct role in these events is unknown. To evaluate the effects of high glucose concentrations and insulinlike growth factor I (IGF-I) on kidney proteoglycan and protein metabolism, we incubated quiescent, subconfluent human fetal mesangial cells for 24 h in serum-free media containing either physiological (5.6-mM) or elevated (25-mM) glucose concentrations with or without 1.3 × 10−9 M IGF-I. In the presence of physiological glucose concentrations, IGF-I stimulated incorporation of [3H]leucine into protein and [35S] sulfate or [3H]glucosamine into proteoglycans. High glucose concentrations significantly amplified IGF-I–mediated stimulation of protein synthesis but totally abolished IGF-I–induced proteoglycan synthesis. The hydrodynamic size and proportions of heparan-35SO4 and chondroitin/dermatan-35SO4 proteoglycans in all experimental media were the same. However, high glucose concentrations decreased the iduronic acid content of dermatan-35SO4. In separate experiments, quiescent cells were cultured for 7 days in media supplemented with 2% fetal calf serum. IGF-I had no effect on mesangial cell proliferation, but as cells reached confluence, high glucose concentrations significantly inhibited cell proliferation. This inhibition was not mimicked by isosmolar concentrations of mannitol. After 7 days, uptake of radioactive precursors into proteoglycans and proteins over 24 h was similar under all culture conditions. However, IGF-I decreased the ratio of [35S] sulfate to [3H]glucosamine in proteoglycans and their glycosaminoglycan side chains. This difference persisted in disaccharides derived by chondroitin ABC lyase digestion of dermatan-35SO4. A higher specific activity of [3H] glucosamine without a change in [35S]sulfate uptake or proteoglycan structure indicated that IGF-I treatment of confluent mesangial cells altered the glucosamine pool size. Thus, in subconfluent human mesangial cells, high concentrations of glucose amplified IGF-I–stimulated protein synthesis but abrogated IGF-I–stimulated proteoglycan synthesis, resulting in a relatively proteoglycan-depleted state. This effect was not seen in cells that had been confluent for several days.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diab.40.10.1346
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1991
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  • 7
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    Online Resource
    Gene Expression Differences in Skin Fibroblasts in Identical Twins Discordant for Type 1 Diabetes
    American Diabetes Association ; 2012
    In:  Diabetes Vol. 61, No. 3 ( 2012-03-01), p. 739-744
    Details
    In: Diabetes, American Diabetes Association, Vol. 61, No. 3 ( 2012-03-01), p. 739-744
    Abstract: Clinical studies suggest metabolic memory to hyperglycemia. We tested whether diabetes leads to persistent systematic in vitro gene expression alterations in patients with type 1 diabetes (T1D) compared with their monozygotic, nondiabetic twins. Microarray gene expression was determined in skin fibroblasts (SFs) of five twin pairs cultured in high glucose (HG) for ∼6 weeks. The Exploratory Visual Analysis System tested group differences in gene expression levels within KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. An overabundance of differentially expressed genes was found in eight pathways: arachidonic acid metabolism (P = 0.003849), transforming growth factor-β signaling (P = 0.009167), glutathione metabolism (P = 0.01281), glycosylphosphatidylinositol anchor (P = 0.01949), adherens junction (P = 0.03134), dorsal-ventral axis formation (P = 0.03695), proteasome (P = 0.04327), and complement and coagulation cascade (P = 0.04666). Several genes involved in epigenetic mechanisms were also differentially expressed. All differentially expressed pathways and all the epigenetically relevant differentially expressed genes have previously been related to HG in vitro or to diabetes and its complications in animal and human studies. However, this is the first in vitro study demonstrating diabetes-relevant gene expression differences between T1D-discordant identical twins. These SF gene expression differences, persistent despite the HG in vitro conditions, likely reflect “metabolic memory”, and discordant identical twins thus represent an excellent model for studying diabetic epigenetic processes in humans.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db11-0617
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2012
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