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)

Chronic elevated glucose levels and activation of the renal renin-angiotensin system have been implicated in the pathogenesis of diabetic nephropathy. We tested the ability of lisofylline (LSF), a novel antiinflammatory compound, to prevent extracellular matrix (ECM) accumulation and growth factor production by human mesangial cells (HMCs) cultured in chronic elevated glucose (HG) or angiotensin II (AngII). HMCs were cultured in normal glucose (NG) (5.5 mm) and in HG (25 mm) for 7 d or with 10-7 m AngII for 4 h with or without LSF. Levels of the ECM protein fibronectin and TGF-beta in media were shown to increase in HG compared with NG. LSF decreased HG-induced fibronectin and TGF-beta production to control levels. Increased expression of collagen type IV and laminin was observed in AngII-cultured HMCs. LSF protected HMCs from the AngII induction of these key matrix proteins. cAMP-responsive binding element phosphorylation was significantly higher in both HG and AngII-cultured HMCs. LSF reduced phosphorylation of both cAMP-responsive binding element and p38 MAPK compared with control. These data demonstrate that LSF protects HMCs from HG- and AngII-mediated ECM deposition by the reduction of matrix protein secretion possibly through regulation of TGF-beta production and modulation of the p38 MAPK pathway. These results suggest that LSF may provide therapeutic benefit for prevention or treatment of diabetic nephropathy.
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PMID:Lisofylline, a novel antiinflammatory compound, protects mesangial cells from hyperglycemia- and angiotensin II-mediated extracellular matrix deposition. 1296

Elevated glucose level is the main cause of extracellular matrix (ECM) derangement in various tissues in diabetes mellitus. The development of diabetic nephropathy is considered to be dependent on profibrotic cytokine, transforming growth factor-beta1 (TGFbeta1). Its excessive activation due to the up-regulation of thrombospondin-1 (TSP-1) in mesangial cells exposed to high glucose contributes to ECM accumulation. However, the role of TSP-1-TGFbeta1 pathway in the development of glucose-induced imbalance of ECM homeostasis in skin connective tissue is not studied. We investigated the response of human skin fibroblasts to elevated glucose level (11.0 and 30.0 mM) in terms of: (1) the expression and secretion of fibronectin (FN) and plasminogen activator inhibitor-1 (PAI-1); (2) the accumulation of hyaluronic acid (HA) in pericellular matrix and in the conditioned medium; (3) TGFbeta1 expression, secretion and activation; (4) TSP-1 expression and secretion. We demonstrated the up-regulation of FN and PAI-1 by elevated glucose and the stimulation of HA accumulation in both cellular compartments. However, we failed to demonstrate the increase of expression, secretion and activation of TGFbeta1, and the increase of TSP-1 expression and secretion in fibroblasts exposed to high glucose. These results show that ECM derangement in skin fibroblasts due to high glucose is not determined by TGFbeta1 and its activation by TSP-1.
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PMID:High glucose-induced alterations of extracellular matrix of human skin fibroblasts are not dependent on TSP-1-TGFbeta1 pathway. 1458 81

Mesangial cell activation is a predominant pathologic feature of diabetic nephropathy that precedes the accumulation of extracellular matrix leading to glomerulosclerosis. For understanding the potential mechanism by which hepatocyte growth factor (HGF) ameliorates diabetic nephropathy, the effects of HGF on mesangial cell activation induced by TGF-beta1 were investigated. Western blot analysis and immunostaining revealed that HGF suppressed alpha-smooth muscle actin expression induced by TGF-beta1 in cultured rat and human mesangial cells. HGF also inhibited TGF-beta1-mediated fibronectin and type I collagen expression. Such action of HGF was dependent on the activation of extracellular signal-regulated kinase-1 and -2 but not on Akt and p38 mitogen-activated protein kinase. HGF did not affect TGF-beta1-mediated Smad2 phosphorylation and its nuclear translocation. However, it rapidly upregulated Smad transcriptional corepressor TG-interacting factor (TGIF) abundance in mesangial cells, which was primarily mediated by stabilizing its protein from degradation. Ectopic expression of TGIF markedly suppressed Smad-mediated activation of TGF-beta1-responsive promoter activity and completely blocked TGF-beta1-induced alpha-smooth muscle actin expression. In vivo, TGIF expression was dramatically downregulated in the glomeruli of diabetic kidneys, and delivery of exogenous HGF induced TGIF expression. These results suggest that HGF specifically antagonizes the profibrotic action of TGF-beta1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF.
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PMID:Hepatocyte growth factor antagonizes the profibrotic action of TGF-beta1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF. 1515 51

The present study was conducted to determine whether iridoid total glycoside from Cornus officinalis was effective in regulating expression of transforming growth factor beta 1 (TGF-beta1) and preventing overdeposition of extracellular matrix (ECM) in a diabetes state. An experimental rat model of diabetic nephropathy (DN) was successfully induced by one intraperitoneal injection of streptozotocin at a dose of 60 mg x kg(-1) and maintained for 12 weeks. All rats had free access to standard chow and water. Four groups: normal control, diabetic control, diabetic rats with aminoguanidine treatment and diabetic rats with iridoid total glycoside treatment were used in this experiment. All treatments were administered by intragastric gavage (ig). At the end of the experiment, serum was collected for ELISA determination of TGF-beta1 protein level; renal cortex was dissected for reverse transcription polymerase chain reaction (RT-PCR) analysis of its mRNA expression; and immunohistochemistry was introduced to observe ECM deposition. A significantly higher level of protein and mRNA expression of TGF-beta1, and also overdeposition of fibronectin and laminin was found in diabetic rats. Both iridoid total glycoside and aminoguanidine were effective in decreasing serum protein level and glomerular mRNA expression of TGF-beta1, and in preventing renal overdeposition of fibronectin and laminin. This study suggests that iridoid total glycoside is a beneficial agent for prevention and therapy of DN.
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PMID:Effects of iridoid total glycoside from Cornus officinalis on prevention of glomerular overexpression of transforming growth factor beta 1 and matrixes in an experimental diabetes model. 1525 32

Diabetic nephropathy affects 30-40% of diabetics leading to end-stage kidney failure through progressive scarring and fibrosis. Previous evidence suggests that tissue transglutaminase (tTg) and its protein cross-link product epsilon(gamma-glutamyl)lysine contribute to the expanding renal tubulointerstitial and glomerular basement membranes in this disease. Using an in vitro cell culture model of renal proximal tubular epithelial cells we determined the link between elevated glucose levels with changes in expression and activity of tTg and then, by using a highly specific site directed inhibitor of tTg (1,3-dimethyl-2[(oxopropyl)thio]imidazolium), determined the contribution of tTg to glucose-induced matrix accumulation. Exposure of cells to 36 mm glucose over 96 h caused an mRNA-dependent increase in tTg activity with a 25% increase in extracellular matrix (ECM)-associated tTg and a 150% increase in ECM epsilon(gamma-glutamyl)lysine cross-linking. This was paralleled by an elevation in total deposited ECM resulting from higher levels of deposited collagen and fibronectin. These were associated with raised mRNA for collagens III, IV, and fibronectin. The specific site-directed inhibitor of tTg normalized both tTg activity and ECM-associated epsilon(gamma-glutamyl)lysine. Levels of ECM per cell returned to near control levels with non-transcriptional reductions in deposited collagen and fibronectin. No changes in transforming growth factor beta1 (expression or biological activity) occurred that could account for our observations, whereas incubation of tTg with collagen III indicated that cross-linking could directly increase the rate of collagen fibril/gel formation. We conclude that Tg inhibition reduces glucose-induced deposition of ECM proteins independently of changes in ECM and transforming growth factor beta1 synthesis thus opening up its possible application in the treatment other fibrotic and scarring diseases where tTg has been implicated.
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PMID:Inhibition of transglutaminase activity reduces extracellular matrix accumulation induced by high glucose levels in proximal tubular epithelial cells. 1532 85

Diabetic nephropathy is characterized by progressive loss of renal function, persistent proteinuria, and relentless accumulation of extracellular matrix leading to glomerulosclerosis and interstitial fibrosis. This study investigated the potential effects of long-term expression of exogenous hepatocyte growth factor (HGF) on normal and diabetic kidneys. Intravenous injection of human HGF gene via naked plasmid vector resulted in abundant HGF protein specifically localized in renal glomeruli, despite an extremely low level of transgene mRNA in the kidney. In uninephrectomized mice made diabetic with streptozotocin, delivery of exogenous HGF gene ameliorated the progression of diabetic nephropathy. HGF attenuated urine albumin and total protein excretion in diabetic mice. Exogenous HGF also mitigated glomerular mesangial expansion, reduced fibronectin and type I collagen deposition, and prevented interstitial myofibroblast activation. In addition, HGF prevented kidney cells from apoptotic death in the glomeruli and tubulointerstitium. Moreover, expression of HGF inhibited renal expression of TGF-beta1 and reduced urine level of TGF-beta1 protein. Therefore, despite the effects of HGF on diabetic nephropathy being controversial, these observations suggest that supplementation of HGF is beneficial in ameliorating diabetic renal insufficiency in mice.
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PMID:Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice. 1546 68

Besides generating renal damage, hypertension plays an important role in the progression of diabetic nephropathy. The fructose-fed rat is a well-established model both of high blood pressure and renal impairment, which is similar to diabetic nephropathy. To clarify the relationship between hypertension, glucose metabolism, and kidney remodeling, we investigated the renal level of Glut 1 and Glut 5, their relation to fibrosis and the effects of an antihypertensive drug on renal damage. Twenty-four male WK rats were divided into three groups: 8 animals received a fructose-enriched diet, 8 a control diet, and 8 animals a high-fructose diet plus amlodipine (5 mg/Kg). After six weeks of treatment, we observed a significant increase in Glut 5, fibronectin, and sorbitol in fructose-fed rats compared with control and amlodipine-treated animals; there was a positive correlation between Glut 5 and fibronectin levels (r = 0.63). Glut 1 levels were similar in all three groups, whereas collagen IV was higher in fructose-fed rats; amlodipine prevented the increase of collagen IV and sorbitol. Collagen I was statistically higher in the fructose group than in the other two groups. Therefore, prolonged fructose feeding results in renal fibrosis via polyol pathway overactivity that can be prevented by means of an antihypertensive drug.
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PMID:Antihypertensive treatment and renal damage: amlodipine exerts protective effect through the polyol pathway. 1547 40

This study investigated the role of advanced glycation end products (AGEs) in mediating protein kinase C (PKC) isoform expression in diabetic nephropathy. In vitro, vascular smooth muscle cells incubated in a high-glucose (25-mmol/l) medium demonstrated translocation and increased expression of PKC-alpha as compared with those from a low-glucose (5-mmol/l) environment. Coincubation with the cross-link breaker ALT-711 and, to a lesser extent, with aminoguanidine, an inhibitor of AGE formation, attenuated the increased expression and translocation of PKC-alpha. Streptozotocin-induced diabetic rats were randomized to no treatment, treatment with ALT-711, or treatment with aminoguanidine. Diabetes induced increases in PKC-alpha as well as in the -betaI, -betaII, and -epsilon isoforms. Treatment with ALT-711 and aminoguanidine, which both attenuate renal AGE accumulation, abrogated these increases in PKC expression. However, translocation of phosphorylated PKC-alpha from the cytoplasm to the membrane was reduced only by ALT-711. ALT-711 treatment attenuated expression of vascular endothelial growth factor and the extracellular matrix proteins, fibronectin and laminin, in association with reduced albuminuria. Aminoguanidine had no effect on VEGF expression, although some reduction of fibronectin and laminin was observed. These findings implicate AGEs as important stimuli for the activation of PKC, particularly PKC-alpha, in the diabetic kidney, which can be directly inhibited by ALT-711.
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PMID:Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-alpha-dependent pathway. 1550 73

The expression of nephropathy in type 2 diabetes has several levels of abnormalities. To define the primary abnormalities of diabetic nephropathy, we conducted an autopsy study of 186 consecutive patients with type 2 diabetes to determine correlations among the aldose reductase gene, renal histopathologies, extracellular matrix, glomerular function, and clinical characteristics. Compared with cases of near-normal renal structure (n = 51) and atypical diabetic glomerulopathy (n = 75), patients with classic diabetic glomerulopathy (n = 60) had advanced glomerular disease, as reflected by elevated plasma creatinine levels (133.2 +/- 59.8 vs. 166.0 +/- 65.7 vs. 243.8 +/- 82.6 micromol/l; P < 0.001), glomerular matrix fractions (20.8 +/- 6.7 vs. 33.5 +/- 16.8 vs. 39.2 +/- 14.3%; P < 0.001), and risk of renal failure (odds ratio [OR] 1 vs. 3.5 vs. 21.4; P < 0.001). Compared with noncarriers of the aldose reductase z-2 allele (n = 92) and z-2 heterozygotes (n = 77), z-2 homozygotes (n = 17) had elevated plasma creatinine (164.1 +/- 73.7 vs. 190.6 +/- 60.9 vs. 241.1 +/- 86.2 micromol/l; P < 0.001) and an increased risk of classic diabetic glomerulopathy (OR 1 vs. 0.9 vs. 3.3; P = 0.026). Overexpression of transforming growth factor-beta1, mesangial cell transdifferentiation by expression of alpha-smooth muscle actin, and aberrant deposition of collagen type IV, fibronectin, and laminin were found in classic diabetic glomerulopathy. These data suggest genetic, biochemical, pathophysiological, and clinical correlations among the aldose reductase gene, extracellular matrix, classic diabetic glomerulopathy, and renal insufficiency. Gene mutation, cellular transdifferentiation, growth factor upregulation, extracellular matrix expansion, and glomerular filtration impairment are the primary abnormalities in type 2 diabetic patients with nephropathy.
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PMID:Association of glomerulopathy with the 5'-end polymorphism of the aldose reductase gene and renal insufficiency in type 2 diabetic patients. 1550 80

Plasma oxidized low-density lipoprotein (OX-LDL) levels are elevated in patients with renal diseases, including diabetic nephropathy. We examined effects of OX-LDL on cell proliferation and extracellular matrix (ECM) production by using normal human mesangial cells. Furthermore, we examined possible involvement of peroxisome proliferator-activated receptor gamma (PPARgamma). Mesangial cell proliferation with OX-LDL, 9-hydroxy-10,12-octadecadienoic acid (9HODE), and 13-hydroxy-9,11-octadecadienoic acid (13HODE), the major components of OX-LDL, were determined by 5-bromo-2'-deoxyuridine (BrdU) or 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) incorporation. The effect of OX-LDL on mesangial cell proliferation with PD98059 pretreatment was determined by BrdU incorporation. Type IV collagen, fibronectin, and PPARgamma expression with OX-LDL or 9HODE or 13HODE was determined by Western blotting. Type IV collagen expression with antisense oligonucleotide against PPARgamma pretreatment was also determined by Western blotting. The effect of PD98059 pretreatment on PPARgamma expression was determined by Western blotting. In mesangial cells exposed to isolated OX-LDL from human plasma, BrdU incorporation was increased, and this increase was deleted by PD98059. Type IV collagen expression was significantly increased by OX-LDL. 9HODE and 13HODE increased BrdU and MTT incorporation into mesangial cells and also increased expressions of Type IV collagen and fibronection, the major components of ECM. PPARgamma expression in mesangial cells was stimulated by 9HODE. The reduction of PPARgamma synthesis by pretreatment of antisense oligonucleotide against PPARgamma remarkably attenuated Type IV collagen synthesis induced by 9HODE. PPARgamma expression induced by 9HODE was also reduced by PD98059 pretreatment. These findings demonstrate that 9HODE, the major component of OX-LDL, stimulates cell proliferation and ECM production of human mesangial cells. In addition, the stimulatory effects are, at least in part, mediated by PPARgamma, which may exist in downstream of ERK1/2 pathway.
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PMID:9HODE stimulates cell proliferation and extracellular matrix synthesis in human mesangial cells via PPARgamma. 1552 42

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