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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes is now the most common cause of progressive kidney failure leading to dialysis or transplantation. The central pathological feature of diabetic nephropathy is accumulation of extracellular matrix within the glomeruli. The factors in the diabetic milieu responsible for extracellular matrix accumulation are not understood. Here we report that in glomeruli of rats made diabetic there is a slow, progressive increase in the expression of transforming growth factor beta (TGF-beta) mRNA and TGF-beta protein. A key action of TGF-beta is induction of extracellular matrix production, and specific matrix proteins known to be induced by TGF-beta were increased in diabetic rat glomeruli. These proteins include an alternatively spliced form of fibronectin, tenascin, and the proteoglycan biglycan. TGF-beta has not previously been implicated in the matrix accumulation that occurs in the diabetic kidney. Glomeruli from humans with diabetic nephropathy also showed a striking increase in immunoreactive TGF-beta protein and deposition of the special form of fibronectin, whereas glomeruli from normal subjects or from individuals with other glomerular diseases (where extracellular matrix accumulation is not a feature) were negative or barely positive. These results implicate TGF-beta in the pathogenesis of diabetic nephropathy.
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PMID:Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. 768 Apr 80

The mechanisms responsible for the increased incidence of congenital malformations in offspring of diabetic mothers are poorly understood. Because the abnormal metabolic milieu of diabetes induces in the adult organism increased synthesis of basement membrane components, and these molecules play a prominent role in morphogenesis, we investigated whether maternal diabetes or high glucose levels disturb extracellular matrix synthesis in rat embryos. In gestational day 11 embryos, maternal diabetes induced a small but significant increase in laminin B1 (127 +/- 40% of control, mean +/- SD, P < 0.02) but not in fibronectin mRNA (101 +/- 26% of control). Day 12 embryos from diabetic mothers showed a larger increment in laminin B1 (179 +/- 91% of control, P < 0.02) and also an increase in fibronectin mRNA (172 +/- 73% of control, P < 0.02). A similar increase in the expression of fibronectin was observed in the kidneys and hearts of day 20 fetuses dissected from diabetic rats. High glucose levels mimicked in vitro the effects of maternal diabetes. Day 9 embryos cultured for 48 h in 50 mM D-glucose showed, akin to the day 11 embryos in vivo, an increase in laminin B1 mRNA (129 +/- 47% of control) and no changes in fibronectin mRNA (106 +/- 35% of control). The finding that maternal diabetes induces increased expression of extracellular matrix components in developing embryos establishes a link with the abnormalities occurring in the chronic complications of diabetes and proposes a new path of investigation for the mechanism of teratogenicity of the diabetic milieu.
Diabetes 1993 Jul
PMID:Maternal diabetes induces increased expression of extracellular matrix components in rat embryos. 768 21

Accelerated protein glycation in diabetes has been mechanistically linked to the pathogenesis of diabetic nephropathy. Because glycated albumin induces abnormalities in cultured mesangial cells that resemble those characterizing the glomerular mesangium in diabetes, and monoclonal antibodies (A717) specific for Amadori-modified glycated albumin prevent these abnormalities, we postulated that in vivo administration of A717 could retard the progression of diabetic nephropathy. To test this hypothesis, diabetic db/db mice and their nondiabetic db/m littermates were treated with eight consecutive weekly injections of 150 micrograms of A717 (Fab fragments) to reduce the elevated plasma glycated albumin concentration, or with irrelevant murine IgG (MIg). Relative to nondiabetics, diabetic mice (MIg treated) manifested proteinuria (3.35 +/- 0.15 vs 0.87 +/- 0.1 mg albumin/mg creatinine), 3.8-fold increase in mesangial matrix fraction, and renal cortical overexpression of mRNAs encoding alpha 1(IV) collagen (2.6-fold increase) and fibronectin (3.8-fold increase). Treatment of db/db mice with A717 significantly reduced the proteinuria (1.52 +/- 0.3 mg/mg creatinine), inhibited mesangial matrix expansion, and attenuated overexpression of matrix mRNAs. The nephropathic protective effects of A717 were independent of any change in blood glucose concentrations. Antibodies unreactive with glycated albumin did not duplicate the beneficial effects of A717. Thus, abrogating the biologic effects of increased glycated albumin with A717 has a salutary influence on the pathogenesis of diabetic nephropathy and has novel therapeutic potential in its management.
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PMID:Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy. 773 97

Low-density lipoprotein (LDL) cholesterol has been implicated in the pathogenesis of glomerulosclerosis in diabetes and other forms of glomerular injury. In the present study we evaluated the effect of LDL on fibronectin synthesis in cultured rat mesangial cells (MCs) and the roles of protein kinase C (PKC) and transforming growth factor-beta (TGF-beta) in mediating this LDL action. In MCs, 25 micrograms to 100 micrograms/ml LDL increased PKC activity within 15 minutes, as reflected by enhanced in situ phosphorylation of the 80 kd myristoylated alanine-rich C kinase substrate protein, a specific endogenous substrate of PKC in MC. The same concentrations of LDL subsequently (18 to 72 hours) enhanced fibronectin synthesis, as reflected by increased incorporation of labeled methionine into fibronectin. GF 109203X, a selective inhibitor of PKC, blocked increases in both PKC activity and fibronectin synthesis induced by LDL in MCs. Furthermore, prior downregulation of PKC to less than 1% of basal activity by exposure of MCs to 0.5 mumol/L phorbol myristate acetate (PMA) also prevented LDL stimulation of fibronectin synthesis. The activation of PKC by LDL seen after 15 minutes of exposure was transient and was not observed after 4 or 48 hours of exposure of MCs to LDL. However, exposure to LDL for 48 hours, but not for 15 minutes or 4 hours, increased both maximal PKC responses to phorbol dibutyrate (PDBu) and tritiated PDBu binding to MCs by 30%. These findings suggest that chronic exposure to LDL increases the total PKC content in MCs and thereby might modulate responses to other PKC agonists. Neither the cyclooxygenase inhibitor piroxicam nor the thromboxane/prostaglandin endoperoxide receptor blocker Sq-29548 altered LDL stimulation of fibronectin synthesis in MCs, suggesting that this action of LDL was not mediated by changes in MC eicosanoid generation. By contrast, antibody to TGF-beta blocked LDL stimulation of fibronectin synthesis in MCs. TGF-beta bioactivity, determined with the mink lung epithelial cell assay, was two to three times higher in the medium of MCs cultured with LDL for 24 to 48 hours as compared with corresponding control values. Total TGF-beta bioactivity examined after heat activation of latent TGF-beta was also two times higher in the medium of MCs exposed to LDL as compared with that of controls. Prior down-regulation of PKC by exposure of MCs to PMA blocked the increases in TGF-beta bioactivity induced by LDL.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Low-density lipoprotein stimulation of mesangial cell fibronectin synthesis: role of protein kinase C and transforming growth factor-beta. 782 50

In diabetes mellitus, thickening of basement membrane in capillaries and small vessels is a well-known finding and important in the progression of diabetic microangiopathy. We evaluated whether the plasma levels of type IV collagen and fibronectin, which are important factors of basement membrane, are related with the presence of diabetic microangiopathy. Plasma type IV collagen and fibronectin levels were measured in 40 healthy controls (Mean +/- SD, age; 50.3 +/- 5.5 yr) and 94 diabetic patients (age; 52.4 +/- 13.5 yr) with and without microvascular complications. The mean plasma levels of type IV collagen (5.3 +/- 2.9 ng/ml) and fibronectin (474.4 +/- 119.4 ug/ml) in diabetic patients were significantly higher (p < 0.01) than in healthy controls (3.7 +/- 1.3 ng/ml and 319 +/- 50.9 ug/ml). The mean plasma level of type IV collagen in diabetic patients with complications (6.6 +/- 3.7 ng/ml) was significantly higher (p < 0.01) than in those without complications (4.3 +/- 1.7 ng/ml) and became higher in more complicated patients. Furthermore, the severity of retinopathy and several indicators of nephropathy such as serum BUN, creatinine and proteinuria were closely associated with plasma type IV collagen level and a significant correlation was found between plasma type IV collagen and creatinine clearance (r = -0.31, p < 0.001). There was no significant difference in plasma fibronectin concentrations, however, between the diabetic patients with complications and those without complications.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasma type IV collagen and fibronectin concentrations in diabetic patients with microangiopathy. 784 83

To elucidate the characteristics of glycoproteins in the mesangial matrix in glomeruli from patients with diabetic nephropathy (DN) in non-insulin-dependent diabetes mellitus (NIDDM), we examined periodic acid-Shiff (PAS) and immunofluorescence staining of types III (III-C), IV (IV-C), V (V-C) and VI (VI-C) collagen, fibronectin (FN), fibrinogen (FBG) and laminin (LN) in the glomeruli of 16 patients with DN and 12 patients with diffuse proliferative glomerulonephritis (DPGN). The percentage of positively staining areas in the glomeruli were calculated using an automatic image analyzer. The percentages of areas positive for PAS, III-C, IV-C, V-C, VI-C or FN in DN were significantly greater than those in DPGN. Moreover, the percentages of PAS-positive areas were significantly correlated with not only IV-C-positive areas, but also FN-positive areas in patients with DN. The percentages of PAS-positive areas were also significantly correlated with the levels of serum creatinine and the degree of proteinuria in these patients. It was concluded that mesangial expansion in this disease might be associated mainly with an increase in IV-C and FN. These changes appear to affect the deterioration of renal function and the appearance of proteinuria, and vice versa.
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PMID:Measurement of the extracellular matrix in glomeruli from patients with diabetic nephropathy using an automatic image analyzer. 785 51

Thromboxane A2 (TXA2) has been implicated in the pathogenesis of progressive glomerulosclerosis and stimulates the synthesis of matrix protein by mesangial cells (MCs). This study examined the role of transforming growth factor beta (TGF-beta) in the mediation of the action of the stable TXA2/prostaglandin (PG) endoperoxide analog U-46619 to stimulate fibronectin (Fn) synthesis in cultured rat MC. Exogenous TGF-beta increased Fn synthesis by MC in a concentration- and time-dependent fashion, as reflected by incorporation of [35S]methionine into immunoprecipitable Fn. Submaximal concentrations of TGF-beta (1-2.5 pmol/l) increased Fn synthesis two- to threefold, a response comparable in magnitude to that observed with a maximal stimulatory concentration (1 mumol/l) of U-46619. Anti-TGF-beta antibody, but not isotypic IgG, blocked the increases in Fn synthesis induced by both U-46619 and exogenous TGF-beta. Endogenous TGF-beta bioactivity in MC culture media, assessed by the mink lung epithelial cell system, was significantly increased by 1 mumol/l U-46619 (1.7 +/- 0.3 pmol/l) compared with that of control media (0.6 +/- 0.1 pmol/l, P < 0.05). Total (active plus latent) TGF-beta bioactivity, assayed after heat activation of latent TGF-beta, was also significantly higher in media of MCs cultured with U-46619 (45 +/- 4 pmol/l) compared with control (24 +/- 4 pmol/l). Thus, U-46619 increased endogenous TGF-beta bioactivity to a level sufficient to account for the enhancement of Fn synthesis observed with U-46619, as reflected by the Fn synthetic response to exogenous TGF-beta.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Mar
PMID:Role for transforming growth factor beta in thromboxane-induced increases in mesangial cell fibronectin synthesis. 788 21

Detection of glycosylated protein in renal tissues was determined in streptozotocin (STZ)-induced diabetic rats using the nitroblue tetrazolium (NBT) reaction. The glycosylation of extra-cellular matrix (ECM) components such as laminin and fibronectin was examined in vitro using the same method. Immunofluorescence staining of laminin or type IV collagen was also performed in renal tissues of STZ-induced diabetic rats. There was no significant difference in the intensity of NBT in renal tissues between 4 week STZ-induced diabetic rats and control rats of the same age. The intensity of NBT staining in the glomerular mesangial areas and capillary walls was marked in 12 week diabetic rats. The mean values of fructosamine measured by the NBT reaction in the glycosylated-laminin and fibronectin were increased dose dependently. In immunofluorescence, laminin and type IV collagen were observed significantly in the glomerular mesangial areas and capillary walls of 12 week diabetic rats. However, there was no significant change in renal histopathology in 4 and 12 weeks diabetic rats. It appears that the non-enzymatic glycosylation and expression of ECM components in glomeruli increased in the early stage of diabetic nephropathy prior to the appearance of marked histologic alterations. In conclusion, non-enzymatic glycosylation of glomerular structural components may play an important role in the initiation of the early stage of renal injuries in diabetes.
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PMID:Detection of glycosylated protein in glomeruli of STZ-induced diabetic rats using the nitroblue tetrazolium (NBT) reaction. 793 13

Erythrocyte-endothelial cell interactions were rediscovered using endothelial cells in culture and radiolabelled erythrocytes. Increased adherence of erythrocytes from patients with sickle cell anaemia was found to be related to the occurrence of vaso-occlusive episodes. In diabetes mellitus and sickle cell anaemia, the adhesion was shown to be potentiated by plasmatic factors such as fibrinogen and fibronectin and to induce endothelial cell activation and enhanced prostacyclin production. The molecular basis of the abnormal adherence of diabetic erythrocytes was shown to be linked to Advanced Glycosylated End-products (AGE) present on the cell membrane and to RAGE 35 receptors exposed by the endothelium. Intercellular Adhesion Molecule (ICAM) was identified as an ubiquitous receptor present on endothelium and involved in leucocyte adhesion and it was more recently demonstrated that erythrocytes infested by Plasmodium falciparum bind to ICAM. This adhesion may be important for the dissemination of Plasmodium falciparum and the complications of the disease. In summary, interactions between endothelium and erythrocytes appear to be involved in the pathophysiology of a number of affections and could constitute a new therapeutic target.
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PMID:Adhesion of erythrocytes to endothelium in pathological situations: a review article. 797 Dec 46

Vascular access occlusion results in significant morbidity in hemodialysis patients. Age, diabetes, and synthetic grafts (polytetrafluoroethylene [PTFE]) have been associated with vascular access occlusion in univariate analysis. However, the independent risk associated with each of these factors has not been assessed adjusting for confounding among the factors or by other variables, such as blood pressure (BP) or hematocrit. The influence of serum lipoprotein(a) [Lp(a)] and fibronectin on vascular access occlusion has not been widely studied despite their theoretical or demonstrated importance in vascular bypass occlusion. In a cohort study of 124 hemodialysis patients monitored for up to 14 months, we reported that Lp(a) values in the upper tertile (> or = 57 mg/dL) were associated with vascular access occlusion risk in white and Hispanic patients, but not in black patients. We now report an expanded analysis of this data set to determine the independent correlates of vascular access occlusion. Variables tested included age, race, gender, diabetes, access type (PTFE v endogenous), treatment time, systolic BP, hematocrit, heparin and erythropoietin dosage, and serum levels of Lp(a) and fibronectin. In univariate analysis, access occlusion was associated with age, diabetes, PTFE, Lp(a) > or = 57 mg/dL, serum fibronectin, and reduced BP. The independent correlates of first access occlusion were determined with the Cox proportional hazards model. Since the overall model included a significant race x Lp(a) interaction term, we stratified by race. In black patients, risk correlated directly with PTFE (P < 0.01) and inversely with systolic BP (P < 0.001), whereas for white and Hispanic patients, age (P = 0.04) and Lp(a) > or = 57 mg/dL (P = 0.05) were associated with increased risk. In summary, vascular access occlusion was found to be associated with a number of factors. Important independent correlates were PTFE and lower BP in black patients, and age and serum Lp(a) > or = 57 mg/dL in white and Hispanic patients. Diabetes mellitus and increased serum fibronectin may contribute additional risk.
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PMID:Correlates of vascular access occlusion in hemodialysis. 797 20


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