UMLS:C0011881 - FACTA Search

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Query: UMLS:C0011881 (diabetic nephropathy)
10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that cultured skin fibroblasts (SFs) from insulin-dependent diabetic mellitus (IDDM) patients with diabetic nephropathy (DN) exhibit both increased proliferation and Na+/H+ antiporter activity. The present study correlated the growth rate and mRNA expression of integrin subunits, extracellular matrix molecules, and transforming growth factor-beta in cultured SFs, with the biopsy determined rate of development of DN lesions ranging from slow to rapid in nine IDDM patients. These varying rates of development of DN lesions were expressed by a mesangial expansion score as estimated by the rate of change in mesangial fraction volume per year. Cultured SF proliferation by direct cell counts positively correlated with mesangial expansion score (r = 0.65; P < 0.05). Expression of cultured SF alpha3 integrin subunit mRNA levels, as well as type I collagen mRNA (P < 0.05 for both), but not transforming growth factor-beta mRNA levels (Northern blot analysis), were also positively correlated with mesangial expansion score. We postulate that these observations of correlations between activities of cultured SFs and the rate of progression of DN lesions may be predictive of the risk to develop clinical DN in IDDM, may be in part genetically regulated, and may be of pathogenetic importance.
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PMID:Relationships of cell proliferation and expression of integrin subunits and type I collagen in skin fibroblasts with renal lesions in patients with IDDM. 946

Glomerulosclerosis and tubulointerstitial fibrosis are common morphological correlates of many end-stage kidneys. There is ample evidence that transforming growth factor-beta (TGF-beta) plays a major role in these alterations by directly stimulating synthesis of many extracellular matrix components and reducing collagenase production, finally leading to renal scarring. Although many factors may induce TGF-beta expression in the kidney, one very interesting aspect is the link between angiotensin II (ANG II) and TGF-beta. Originating from observations in vascular smooth muscle cells, there are now several additional studies showing that ANG II stimulates TGF-beta expression in the kidney. Although cell culture studies have convincingly demonstrated that the vasoactive peptide directly stimulates transcription as well as bioactivation of TGF-beta, the in vivo evidence is more indirect. Nevertheless, there are several pathophysiological situations including unilateral ureteral obstruction, chronic cyclosporin A nephrotoxicity, various models of hypertension, and probably diabetic nephropathy in which ANG II-mediated TGF-beta induction has been demonstrated to play an important role in the progression of the disease. The fascinating aspect of this relationship between ANG II and TGF-beta is the fact that hemodynamic changes as well as structural changes are linked together generating a unifying model of progression of chronic renal failure with ANG II as the key player. Angiotensin-converting enzyme (ACE) inhibitor and the more recently introduced AT1-receptor blocker may be potential drugs to interfere with this ANG II-mediated TGF-beta expression. Therefore, these drugs should not only be considered as antihypertensive medications, but should rather be viewed as renoprotective substances influencing renal remodeling by preventing local TGF-beta expression.
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PMID:Link between angiotensin II and TGF-beta in the kidney. 952 2

We investigated the effect of inhibition of a polyol pathway on the glucose-induced increase in transforming growth factor-beta (TGF-beta) production and activity of protein kinase C (PKC) in cultured human mesangial cells (MCs). The exposure of MCs to 33 mmol/l glucose resulted in an increase in TGFbeta production, measured by ELISA, compared with 5 mmol/l glucose. The glucose-induced increase in TGF-beta was prevented by concomitant incubation with epalrestat, an aldose reductase inhibitor (ARI), in a dose-dependent manner at a concentration of more than 10(-6) mol/l. Moreover, the glucose-induced enhancement of PKC activity in the membrane fraction of MCs was also abolished by epalrestat. The addition of epalrestat to MCs cultured with 5 mmol/l glucose showed no demonstrable effects on TGF-beta production and PKC activity. These results provide direct evidence for linkages between derangements in polyol pathway and glucose-induced overproduction of TGF-beta and enhancement of PKC activity in MCs. Accordingly, the effect of an ARI on these metabolic abnormalities in MCs may justify its clinical application for treatment of diabetic nephropathy.
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PMID:An aldose reductase inhibitor prevents glucose-induced increase in transforming growth factor-beta and protein kinase C activity in cultured mesangial cells. 954 Nov 79

Diabetes mellitus is a complex disease characterised by chronic hyperglycaemia responsible for complications affecting the kidneys, eyes, peripheral nerves and micro- and macrovascular systems. Von Willebrand factor (vWf), a multimeric glycoprotein mainly synthesised by endothelial cells, is involved in platelet adhesion and aggregation and acts as the carrier of coagulation factor VIII in plasma. Increased levels of vWf, reflecting activation of or damage to endothelial cells, have been described in association with atherosclerosis and diabetes. vWf appears to be a predictive marker of diabetic nephropathy and neuropathy, although not of retinopathy, which suggests that endothelial dysfunction precedes the onset of diabetic microangiopathy. This dysfunction could be especially involved in the pathogenesis of renal abnormalities of diabetes. vWf is not a predictive marker of macroangiopathy when diabetes is associated with atherosclerotic risk factors. In the presence of chronic diabetic complications, vWf levels are not associated with any grade of retinopathy but increase with the severity of nephropathy and would appear to be a risk factor for macrovascular mortality in these patients. The endothelial dysfunction of diabetes can generate atherosclerotic lesions responsible for damage to the arterial wall, atheroma and formation of platelet microaggregates. Concomitant with high vWf levels, other possible mechanisms of endothelial damage include reduced synthesis or release of nitric oxide, hyperglycaemic pseudohypoxia and protein kinase-C activation, increased synthesis of proteins bearing advanced glycosylation end-products or transforming growth factor-beta (TGF-beta) activation of coagulation and inhibition of fibrinolysis. At present, it is not known whether high vWf levels are inherent to the physiopathology of diabetes, nor whether diabetes induces endothelial dysfunction through other pathways. However, since angiopathy resulting from endothelial dysfunction is the main cause of morbidity and mortality in diabetic patients, appropriate therapy is necessary to reduce these complications. Glycaemic control seems to be insufficient to normalise plasma vWf, whereas a decrease can be obtained by ingestion of diets rich in oleic acid or by treatment with statins. Inhibition of the binding of vWf to the GPlba receptor by synthetic peptides, aurin tricarboxylic acid or monoclonal antibodies has been proposed to prevent the thrombosis induced by high levels of plasma vWf. Thus, vWf probably represents an interesting target for the inhibition of thrombosis in diabetes.
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PMID:Von Willebrand factor in diabetic angiopathy. 980 43

The core protein of the proteoglycan decorin binds and neutralizes transforming growth factor-beta (TGF-beta). Activation of TGF-beta is crucial to tissue injury in diabetic nephropathy, but it is not currently known whether decorin plays a role in this disease. Mouse kidney cortex demonstrates more than a twofold increase in decorin mRNA after 1, 2, 3, and 6 wk of streptozotocin diabetes. Various mouse and rat renal cell types are studied in culture under normal or high-glucose conditions. Mouse glomerular mesangial and proximal tubular epithelial cells constitutively express decorin, and high glucose (450 mg/dl) increases decorin mRNA fourfold compared with 100 mg/dl glucose. Unlike rat mesangial cells, rat glomerular epithelial and endothelial cells do not constitutively express decorin, and no induction is observed in high glucose. When mouse mesangial and proximal tubular cells are exposed to TGF-beta1 (1 ng/ml), decorin mRNA is significantly decreased. Our findings suggest that the increased decorin expression in the diabetic kidney may counteract the hypertrophic and prosclerotic effects of increased TGF-beta levels and that a negative feedback loop may exist between decorin and TGF-beta.
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PMID:Increased decorin mRNA in diabetic mouse kidney and in mesangial and tubular cells cultured in high glucose. 981 41

Altered growth of renal cells is one of the early abnormalities detected after the onset of diabetes. Cell culture studies whereby renal cells are exposed to high glucose concentrations have provided a considerable amount of insight into mechanisms of growth. In the glomerular compartment, there is a very early and self-limited proliferation of mesangial cells with subsequent hypertrophy, whereas proximal tubular cells primarily undergo hypertrophy. There is overwhelming evidence from in vivo and cell culture studies that induction of the transforming growth factor-beta (TGF-beta) system mediates the actions of high ambient glucose and that this system is pivotal for the hypertrophy of mesangial and tubular cells. Other factors such as hemodynamic forces, protein glycation products, and several mediators (for example, angiotensin II, endothelin-1, thromboxane, and platelet-derived growth factor) may further amplify the synthesis of TGF-beta and/or the expression of its receptors in the diabetic state. Cellular hypertrophy can be characterized by cell cycle arrest in the G1 phase. The molecular mechanism arresting mesangial cells in the G1 phase of the cell cycle is the induction of cyclin-dependent kinase (CdK) inhibitors such as p27Kip1 and p21, which bind to and inactivate cyclin-CdK complexes responsible for G1-phase exit. High-glucose-induced activation of protein kinase C and stimulated TGF-beta expression appear to be essential for stimulated expression of p27Kip1. In addition, a decreased turnover of protein caused by the inhibition of proteases contributes to hypertrophy. The development of irreversible renal changes in diabetes mellitus such as glomerulosclerosis and tubulointerstitial fibrosis is always preceded by the early hypertrophic processes in the glomerular and the tubular compartments. It may still be debated whether diabetic renal hypertrophy will inevitably lead to irreversible fibrotic changes in the absence of other factors such as altered intraglomerular hemodynamics and genetic predisposition. Nevertheless, understanding cellular growth on a molecular level may help design a novel therapeutic approach to prevent or treat diabetic nephropathy effectively.
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PMID:Molecular mechanisms of diabetic renal hypertrophy. 1043 77

Renal tubular epithelial cells and interstitial fibroblasts are active participants in tubulointerstitial fibrosis, the best correlate of decreased glomerular filtration in diabetic nephropathy. It was reported previously that high ambient glucose stimulates transforming growth factor-beta (TGF-beta) mRNA and bioactivity, promotes cellular hypertrophy, and increases collagen synthesis in proximal tubular cells. This study evaluates the effects of high glucose and TGF-beta on the behavior of murine renal cortical fibroblasts (TFB) in culture. High glucose (450 mg/dl) significantly increased [3H]-thymidine incorporation (by 60 to 80% after 24 to 72 h) and cell number, without significantly increasing cell death when compared with normal glucose (100 mg/dl). There also was a transient increase in the mRNA of the c-myc and egr-1 early-response genes. Exogenous TGF-beta1 was promitogenic rather than antiproliferative in contrast to other renal cell types. Northern blot analysis demonstrated constitutive expression of TGF-beta1, -beta2, and -beta3 transcripts. Exposure to high glucose increased all three TGF-beta isoforms in a time-dependent manner. High glucose as well as exogenous TGF-beta1 also increased [3H]-proline incorporation, alpha2(I) collagen mRNA, and type I collagen protein (measured by immunoassay). Treatment with a neutralizing pan-selective monoclonal anti-TGF-beta antibody markedly attenuated the stimulation by high ambient glucose of thymidine incorporation, TGF-beta1 mRNA, and type I collagen mRNA and protein levels. It is concluded that high ambient glucose and exogenous TGF-beta1 share similar actions on renal fibroblasts. Moreover, the stimulation of cell proliferation and collagen type I synthesis in these cells by high ambient glucose are mediated by activation of an autocrine TGF-beta system.
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PMID:High glucose stimulates proliferation and collagen type I synthesis in renal cortical fibroblasts: mediation by autocrine activation of TGF-beta. 1047 40

The renoprotective effect of captopril on progression of diabetic nephropathy was demonstrated by the Collaborative Study Group Captopril Trial and might be independent of blood pressure. Because angiotensin II is known to stimulate the prosclerotic cytokine, transforming growth factor-beta (TGF-beta), we postulated that the renoprotective effect may be due to inhibition of TGF-beta1 production. TGF-beta1 levels were measured in serum at baseline and 6 months from patients in the captopril trial. TGF-beta1 analyses were performed on all available patient sera. Analysis was performed between the percent change in TGF-beta1 levels during the first 6 months versus the percent change in glomerular filtration rate (GFR) in the subsequent 2 years. TGF-beta1 levels increased by 11% (P = 0. 003) in the placebo group (n = 24), whereas there was a decrease of 14% (P = 0.01) in the captopril group (n = 34). There was an inverse correlation between the percent change in TGF-beta1 levels during the first 6 months and the percent change in GFR over the ensuing 2-year period in patients from both the placebo (r = -0.55, P = 0. 005) and captopril groups (r = -0.45, P = 0.008). In patients with initial GFR below 75 mL/min, there was an even stronger correlation in percent change in TGF-beta1 levels and percent change in GFR in both placebo (n = 9, r = -0.69, P = 0.03) and captopril groups (n = 21, r = -0.73, P = 0.0001). Our data suggest that captopril decreases TGF-beta1 levels in diabetic nephropathy and that changes in TGF-beta1 levels may predict the course of diabetic nephropathy.
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PMID:Captopril-induced reduction of serum levels of transforming growth factor-beta1 correlates with long-term renoprotection in insulin-dependent diabetic patients. 1056 Nov 56

Recent experimental work implicates transforming growth factor-beta (TGF-beta) as an aetiologic mediator of diabetic nephropathy and the ubiquitous glucose transporter GLUT1 as an important permissive factor for the tissue injury caused by hyperglycaemia. High ambient glucose increases GLUT1 expression and glucose transport activity when compared with physiologic glucose concentrations. Treatment of rat mesangial cells with TGF-beta up-regulates GLUT1 mRNA and protein levels and significantly increases glucose uptake. Addition of neutralizing anti-TGF-beta antibody prevents the stimulatory effects of high glucose on GLUT1 expression. Cultured rat mesangial cells transduced with the human GLUT1 gene and thus overexpressing the GLUT1 protein show marked increase in glucose uptake and the synthesis of extracellular matrix molecules, even when grown in normal ambient glucose concentrations. Thus, TGF-beta and GLUT1, two proteins that are up-regulated in glomerular mesangial cells in a hyperglycaemic milieu, can influence the expression of one another. It is therefore fair to conclude that, with successful interruption of the TGF-beta-GLUT1 axis, the beneficial effects of strict glucose control on the development of diabetic nephropathy could likely be augmented.
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PMID:GLUT1 and TGF-beta: the link between hyperglycaemia and diabetic nephropathy. 1097 17

Although the glomerulus, particularly the mesangium, has been the focus of intense investigation in diabetes, tubulointerstitial injury is also a major feature of diabetic nephropathy and an important predictor of renal dysfunction. The renal tubule in diabetes is subject to both direct and indirect pathogenetic influences as a consequence of its position in the nephron and its resorptive function. On exposure to glucose, proximal tubular cells elaborate vasoactive hormones, including angiotensin II and injurious cytokines such as transforming growth factor-beta (TGF-beta), as well as extracellular matrix proteins. In turn, angiotensin II may further increase TGF-beta expression in both proximal tubular and interstitial cells, thus amplifying the stimulus to fibrogenesis in the renal tubulointerstitium. In addition to these mostly direct influences, the renal tubule, particularly its proximal segment, is exposed to glomerular effluent. In the diabetic state, this includes large quantities of advanced glycation end products and glucose and, at later stages in the evolution of diabetic nephropathy, protein, all of which are factors that may induce TGF-beta expression and fibrosis. Diabetic nephropathy should therefore be viewed as a disease affecting the entire nephron. Continued exploration into tubulointerstitial disease in addition to glomerular injury in diabetes may help provide further insights into the pathogenesis of diabetic nephropathy and additional targets for therapeutic intervention.
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PMID:The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? 1057 71

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