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

We investigated the intrarenal distribution of transforming growth factor-beta 1 (TGF-beta 1) protein and the TGF-beta 1 mRNA levels in the glomeruli and renal cortex of Wistar rats with streptozotocin-induced diabetes before and after the onset of diabetic nephropathy. Monthly urinary albumin excretion, glomerular filtration rate, glomerular volume, renal histology and immunohistochemical reaction for type-I collagen were also studied. The results showed progressively higher glomerular immunohistochemical TGF-beta 1 staining in rats with a diabetes duration of 24 and 40 weeks which was correlated with albuminuria (r = 0.905, p < 0.01) and was temporally associated with the appearance of glomerular deposition of total and type-I collagen. The glomerular content of TGF-beta 1 mRNA was higher in rats diabetic for 20 weeks while lower cortical RNA-TGF-beta 1 levels were found in rats with a diabetes duration of 1-40 weeks. These data suggest that this polypeptide may be an important mediator of diabetic glomerulosclerosis.
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PMID:Transforming growth factor-beta in the development of rat diabetic nephropathy. A 10-month study with insulin-treated rats. 888 39

Diabetic nephropathy is preceded by 'hyperfiltration' mediated by dilatation of the afferent arterioles to the glomeruli by means of IGF-1, prostaglandins, bradykinin, nitric oxide and atrial natriuretic peptide, together with constriction of the efferent arterioles by local thromboxane A2. Raised glomerular intracapillary pressures might then contribute to glomerulosclerosis, but in any case there is permeability of the vascular endothelium. AGEPs and lipid peroxides can explain this. AGEPs, or simply intermittently high levels of glucose, also account for synthesis of extracellular matrix proteins that lead to thickening of the basement membrane and glomerulosclerosis. Another glucose product, glucosamine-6-phosphate, is formed when there is hexosamine flux along with insulin resistance in tissues, and is implicated in glomerulosclerosis, since it also stimulates TGF-beta transcription. In seeking to explain proteinuria, depletion of heparan sulphates from the endothelial cells and GBM is now established as a principal cause. In addition to a high glucose reducing the synthesis of heparan sulphates, it has now been shown that high glucose may depress the synthesis of heparin sulphate proteoglycan.
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PMID:How does hyperglycaemia predispose to diabetic nephropathy? 930 34

The earliest manifestations of type I diabetic nephropathy include mesangial matrix expansion, basement membrane thickening, and renal hypertrophy. Transforming growth factor (TGF)-beta, a potent inducer of matrix protein synthesis, is a prime candidate to mediate the glomerular changes observed in diabetes. However, the temporal expression of TGF-beta and matrix proteins during the early stage of diabetic nephropathy has not been clearly defined. Using in situ hybridization and immunohistochemistry, we determined the expression of TGF-beta and type IV collagen mRNAs and proteins in glomeruli and interstitium of diabetic rats 3, 7, and 14 days after streptozotocin (STZ) administration. There was a marked increase in the expression of TGF-beta and alpha1(IV) procollagen mRNAs in glomerular and tubulointerstitial cells as early as 3 days after induction of diabetes, an effect that persisted for 14 days. A concomitant increase in TGF-beta and type IV collagen proteins was also observed at each time point. Insulin treatment substantially inhibited the increased expression of TGF-beta and collagen type IV mRNAs and proteins. We conclude that TGF-beta is increased in glomeruli during the early phase of rapid renal growth in diabetes. These findings suggest that TGF-beta may be a key factor involved in the pathogenesis of basement membrane thickening and extracellular matrix accumulation. Inhibition of TGF-beta and type IV collagen expression by insulin treatment suggests that they may be useful structural markers for determining the efficacy of therapeutic intervention during early diabetic nephropathy.
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PMID:Expression of transforming growth factor-beta and type IV collagen in early streptozotocin-induced diabetes. 903 5

The role that advanced glycosylation end-products (AGEs) may play in the development of diabetic nephropathy is still not completely understood. In order to elucidate the nature of their effect, the consequences of exogenously administered AGEs on extracellular matrix gene expression were examined in mice by competitive PCR. Normal adult mice receiving repeated injections of AGEs had an increase in the expression of genes coding for type IV collagen and laminin in the glomeruli. The increase was accompanied by up-regulation of TGF-beta 1 but not PDGF-B expression. The expression of smooth muscle and beta-actin did not change, showing that the increase in gene expression was specific for genes implicated in the early stages of diabetic nephropathy. The co-administration of aminoguanidine, a drug that inhibits AGEs cross-links, prevented the up-regulation of gene expression in AGEs-injected mice. Thus, AGEs can induce extracellular matrix genes in the absence of hyperglycaemia.
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PMID:Administration of AGEs in vivo induces extracellular matrix gene expression. 904 10

Proximal tubular epithelial cells are the most abundant cells in the renal cortex, and recent studies suggest that they may play an important role in initiating pathological changes in renal disease. Transforming growth factor (TGF)-beta 1 has been implicated as a major factor controlling the development and progression of renal fibrosis in numerous diseases, including diabetic nephropathy. We have recently demonstrated that human proximal tubular epithelial cells synthesize and secrete TGF-beta 1 after the sequential addition of both 25 mmol/L D-glucose and platelet-derived growth factor (PDGF). The present study examines the control of this synthesis and in particular the polar requirements of the stimulation and the direction of release of the protein. A proximal tubular cell line (LLC-PK1) was cultured on porous tissue culture inserts. Confluent cells were exposed to 25 mmol/L D-glucose on either their apical or basolateral aspect. TGF-beta 1 mRNA induction (reverse transcriptase polymerase chain reaction) occurred only after basolateral exposure. Similarly, TGF-beta 1 synthesis and secretion was induced only by the subsequent addition of PDGF to the basolateral aspect of the cells. In contrast, TGF-beta 1 protein secretion was detected equally in the apical and basolateral compartments. This effect was maximal after 12-hour PDGF stimulation and represented a threefold increase over controls for TGF-beta 1 in both the apical and basolateral compartments (n = 3, P < 0.05 versus control). The glucose transporter inhibitors phlorizin and phloretin were used to investigate the role of specific D-glucose transport proteins. Application of either basolateral phlorizin or phloretin at the time of addition of 25 mmol/L D-glucose to the same compartment inhibited TGF-beta 1 synthesis in response to PDGF. Maximal inhibition was achieved at 0.5 mmol/L of either inhibitor (phlorizin percent inhibition of apical TGF-beta 1, 75%, P = 0.015, and of basolateral TGF-beta 1, 78%, P = 0.015; phloretin percent inhibition of apical TGF-beta 1, 68%, P = 0.03, and of basolateral TGF-beta 1, 79%, P = 0.001, n = 5, P versus control). No inhibition was seen with apical application of either inhibitor. These data demonstrate that the priming of proximal tubular cells for TGF-beta 1 synthesis occurs only after basolateral exposure of the cells to 25 mmol/L D-glucose. This mechanism is dependent on the activity of the basolateral D-glucose transporter GLUT-1. In another series of experiments, TGF-beta 1 synthesis in response to the addition of basolateral PDGF was also induced after basolateral pretreatment with D-galactose but not 2-deoxy-D-glucose. This priming effect demonstrates the dependence of this response on glucose metabolism by the cells, not simply the activity of the GLUT-1 transporter, as both 2-deoxy-D-glucose and D-galactose are transported by GLUT-1, although only the latter is metabolized. The extrapolation of these results to diabetic nephropathy would suggest that it is changes in the interstitial concentration of glucose rather than the urinary glucose level that likely modulate the synthesis of the profibrotic cytokine TGF-beta 1 and thereby influence the progression of interstitial fibrosis.
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PMID:Polarity of stimulation and secretion of transforming growth factor-beta 1 by cultured proximal tubular cells. 906 Aug 45

Hypertension, diabetes mellitus and chronic glomerular diseases reportedly cause in excess of 80% of the incident cases of end-stage renal disease (ESRD) in the U.S. The factors that initiate progressive renal failure in patients with these disorders remain unknown. Several investigators have reported enhanced synthesis and activity of cytokines in the kidneys of patients with renal failure. The ensuing inflammation and fibrosis have been postulated to contribute to the development of progressive renal failure. There is also abundant evidence supporting the contribution of genetic factors in ESRD susceptibility based upon the strong familial clustering of ESRD, particularly in African Americans. Therefore, genetic linkage analysis may be useful to evaluate the role of candidate genes in several cytokine cascades that could contribute to the pathogenesis of chronic renal failure. We tested for genetic linkage between eight cytokine candidate genes and chronic renal failure in a collection of African American sibling pairs concordant for ESRD. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta 1, TGF-beta 2 and TGF-beta 3, and tumor necrosis factor (TNF)-alpha and TNF-beta candidate genes were selected for analysis due to their putative roles in diabetic renal disease and chronic glomerulonephritis. The interleukin-1 receptor antagonist gene (IL1RN) was also genotyped due to its reported association with diabetic nephropathy. Non-parametric (genetic model independent) affected sib pair linkage analysis was used to evaluate evidence for linkage. In order to genotype TGF-beta 3, we identified four closely linked, previously unidentified, highly polymorphic microsatellite loci near the TGF-beta 3 gene. Linkage of ESRD and transforming growth factor beta 2 polymorphisms on human chromosome 1 approached significance for non-diabetic nephropathy (predominantly chronic glomerular disease, hypertensive nephrosclerosis and unknown etiology) (P = 0.08), but showed no linkage to diabetic nephropathy. The other candidate loci did not demonstrate linkage to ESRD in the total population or in the subgroups with diabetic or non-diabetic etiologies of ESRD. The IL1RN gene did not show significant evidence for linkage to ESRD; however, we did confirm an association between allele 2 of IL1RN and ESRD (as reported in diabetic nephropathy). Overall, these results suggest that these growth factor loci do not make major contributions to the pathogenesis of ESRD in African Americans.
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PMID:Genetic linkage analysis of growth factor loci and end-stage renal disease in African Americans. 906 16

Accumulation of matrix proteins is a prominent feature of diabetic nephropathy. Glomerular visceral epithelial cells (GVECs) are important contributors to extracellular matrix (ECM) production in the glomerulus. Factors involved with increased accumulation of ECM proteins are high glucose, angiotensin II (ANG II), and transforming growth factor (TGF)-beta. Therefore, we investigated the effects of high glucose and ANG II on fibronectin and TGF-beta production by human GVECs in vitro. We found that ANG II had no effect on the production of fibronectin and TGF-beta by GVECs. Using reverse transcriptase-polymerase chain reaction analysis, no ANG II receptor could be detected on these cells. However, high glucose induced a twofold increase in fibronectin (P < 0.01) and a three- to sixfold increase in TGF-beta (P < 0.001) production. Similar results were obtained by analyzing the mRNA levels of fibronectin (increased 2.7-fold) and TGF-beta (increased 3.5-fold). Addition of increasing concentrations of rTGF-beta to control cells resulted in increased fibronectin production. Neutralizing antibodies against TGF-beta significantly reversed the increase in fibronectin protein and mRNA caused by high glucose back to control levels. We conclude that high glucose concentrations stimulate the synthesis of fibronectin and that this effect is mediated by induction of TGF-beta. These results suggest that in diabetic nephropathy, high glucose levels play a role in changing the matrix composition of the glomerular basement membrane through induction of TGF-beta. Our results indicate that a contribution to this process by an effect of ANG II on GVECs seems unlikely.
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PMID:Regulation of glomerular epithelial cell production of fibronectin and transforming growth factor-beta by high glucose, not by angiotensin II. 913 52

The purpose of the study was to assess TGF-beta and IL-6 urinary excretion (measured with EIA) in 12 IDDM patients (7 F, 5 M, age 20-49 yrs, mean = 33.08) with albuminuria or microalbuminuria. Control group consists of 27 IDDM patients (12 F, 15 M, age 24-59 yrs. mean = 39.5) without albuminuria or microalbuminuria. Urinary excretion of IL-6 was significantly higher (p < 0.05) in IDDM patients with albuminuria (mean = 7.43 +/- 8.29 pg/mg creatinine) than in control group (mean = 3.74 +/- 2.64 pg/mg creatinine). Urinary excretion of TGF-beta was also higher (but not significantly in IDDM patients with albuminuria or microalbuminuria (mean = 42.0 +/- 30.0 pg/mg creatinine) than in control group (mean = 27.0 +/- 20.0 pg/mg creatinine). The data indicate that IL-6 and TGF-beta could be involved in the development of diabetic nephropathy.
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PMID:[Increased urinary excretion of transforming growth factor beta and interleukin-6 in patients with diabetic nephropathy]. 913 74

It has been demonstrated that cultured mesangial cells (MC) express latent transforming growth factor (TGF)-beta binding protein (LTBP) mRNA, and that LTBP might be essential for the extracellular matrix (ECM) accumulation stimulated by TGF-beta in cultured MC. We performed a study to test the pathophysiological role of LTBP in mesangial ECM accumulation in human glomerulonephropathies. The expression of LTBP in 64 renal biopsies of patients with renal diseases was examined by immunohistochemical staining with the specific antibody raised against human LTBP. The biopsy specimens were divided into three groups: Group 1, IgA nephropathy; Group 2, IgA negative mesangial proliferative glomerulonephritis, which mainly consisted of diabetic nephropathy and lupus nephritis; and Group 3, non-proliferative nephropathy, which consisted of minimal change and membranous nephropathy. Immunohistochemical staining of LTBP was significantly detected in mesangial/paramesangial area of glomerulus in Group 1, but not observed in Group 2 or Group 3. The intensity of staining was well related to the grade of mesangial ECM accumulation in Group 1. These findings suggest that the LTBP-TGF-beta complex may play a pivotal role in ECM accumulation in IgA nephropathy, and that modification of LTBP-ECM interaction might provide a new therapeutic strategy against the progression of glomerulosclerosis.
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PMID:Immunohistochemical localization of latent transforming growth factor-beta binding protein in IgA nephropathy. 940 53

We studied the urinary excretion of transforming growth factor-beta 1 (TGF-beta 1), platelet-derived growth factor-BB (PDGF) and fibronectin (FN) in 104 patients (52 normoalbuminuric, 24 microalbuminuric, and 28 with overt diabetic nephropathy) with insulin-dependent diabetes mellitus (IDDM) of a long duration and in 30 non-diabetic controls. IDDM patients had higher urinary excretion of TGF-beta 1, PDGF and FN compared to controls. Urinary excretion of TGF-beta 1 and PDGF was elevated in all IDDM subgroups, while FN excretion was significantly increased only in patients with macroalbuminuria. Urinary excretion of TGF-beta 1 and FN did not differ between normoalbuminuric IDDM patients with long duration of diabetes, a group at low risk of ever developing diabetic nephropathy, and IDDM patients with incipient or overt diabetic nephropathy. Excretion of PDGF was significantly higher in patients with micro- and macroalbuminuria compared to normoalbuminuric patients, but there was a considerable overlap between the groups. In conclusion, although longitudinal follow-up studies are needed to further clarify the issue, our results in long-standing IDDM do not support a hypothesis of urinary excretion of TGF-beta 1, PDGF or FN to predict development of diabetic nephropathy.
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PMID:Urinary excretion of TGF-beta 1, PDGF-BB and fibronectin in insulin-dependent diabetes mellitus patients. 940 57


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