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)

High glucose (HG) causes glomerular mesangial cell (GMC) growth, production of transforming growth factor (TGF)-beta, and increased synthesis of matrix proteins such as fibronectin, contributing to diabetic nephropathy. We recently found that exposure of cells to HG also activates the growth-promoting enzyme janus kinase 2 (JAK2) and its latent signal transducers and activators of transcription (STAT) transcription factors (STAT1, STAT3, and STAT5). Our purpose was to determine the effect that inhibition of JAK2 and these STAT transcription factors has on the HG-induced increase in TGF-beta and fibronectin synthesis in GMC. Exposure of GMC to 25 mmol/l glucose caused the activation of JAK2, STAT1, STAT3, and STAT5 plus an increase in TGF-beta and fibronectin synthesis, as compared with 5.5 mmol/l glucose. This HG-induced increase in synthesis of TGF-beta and fibronectin was prevented by concomitant incubation with AG-490, a specific JAK2 inhibitor. The HG-induced JAK2, STAT1, and STAT3 tyrosine phosphorylations in GMC were also abolished by AG-490. Preincubation of GMC cultured in 25 mmol/l glucose with a specific JAK2 or STAT1 antisense oligonucleotide also prevented both TGF-beta and fibronectin synthesis. These results provide direct evidence for linkages between JAK2, STAT1, and the glucose-induced overproduction of TGF-beta and fibronectin in GMC.
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PMID:Inhibition of the Jak/STAT signaling pathway prevents the high glucose-induced increase in tgf-beta and fibronectin synthesis in mesangial cells. 1245 7

SEVERAL MECHANISMS: The progression in renal failure first implies hemodynamic mechanisms and among which angiotensin II has a central role, but also an increase in proteinuria and the induction of many inflammatory and mitogenic mediators that enhance fibrosis (TGF-beta), an effect stimulating the thrombotic mechanism. Among these factors of progression in renal failure, hypertension and proteinuria are the two major factors. Proteinuria is "nephrotoxic" and leads to glomerular and tubulo-interstitial lesions. THE ROLE OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS: Angiotensin-converting enzyme inhibitors (ACE) affect the different mechanisms that lead to glomerulosclerosis: antihypertensive effect, with the normalisation of blood pressure having demonstrated its determining role in the production of nephrosis in various epidemiological studies; hemodynamic effect with a decrease in glomerular capillary pressure, in the filtration fraction, and inhibition of the bradykinin deterioration; antiproteinuric effect superior to that of other anti-hypertensive drugs (excepting angiotensin II-receptor antagonists). Two indications ACE inhibitors have demonstrated their efficacy in slowing the progression of renal failure in two large pathological fields: diabetic nephropathy in which this effect is demonstrated in type I diabetes, although the results are not as obvious in type II diabetes in which the nephropathy is multi-factor. The recent French and American recommendations are that ACE inhibitors should be used in first intention in diabetic nephropathies and aimed at tight blood pressure control; non-diabetic nephropathies Two pivotal studies have demonstrated the efficacy of ACE inhibitors in nephropathies whatever their type. These data have led to propose ACE inhibitors in first intention in patients exhibiting chronic nephropathies, whether hypertensive or not THE COMBINATION WITH OTHER HYPERTENSIVE DRUGS: Calcium channel blockers have a beneficial trophic effect in renoprotection and can be combined with ACE inhibitors, particularly in the case of diabetic nephropathies. ACE inhibitors and angiotensin II-receptor antagonists have comparable effect on hemodynamics and glomerulosclerosis factors. Clinically, the decrease in proteinuria is identical. Endothelin antagonists have also been studied in renoprotection and appear to have a beneficial effect when combined with ACE inhibitors. GLOBALLY: ACE inhibitors remain the only treatment with demonstrated long-term efficacy in the progression of chronic renal failure. However, the concept of renoprotection needs to be widened to all the factors implied in the progression of chronic renal failure, and ACE inhibitors only represent one aspect of treatment. The role of angiotensin II-receptor antagonists, alone or combined, is clearly promising.
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PMID:[The effect of angiotensin-converting enzyme inhibitors on the progression of chronic renal failure]. 1246 54

Transformation growth factor (TGF-beta) is a cytokine, which takes part in many clinical conditions linked to different chronic disease states. Its production is regulated by genes and polymorphism of TGF-beta gene individually predetermines levels of its production. TGF-beta is produced by a number of normal, predominately haemopoietic and tissue cells. Moreover, it controls cell proliferation and differentiation, and namely it stimulates fibrogenesis. Profibrogenic efficacy plays a physiological role in wound healing and it is implicated in a spectrum of disease states, such as diabetic nephropathy, chronic glomerulonepthritis, lung fibrosis, or postirradiation fibrosis. In kidney transplant recipients. TGF-beta has been suggested to be involved in the chronic rejection pathogenesis by enhancing fibrogenesis.
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PMID:[Transforming growth factor (TGF-beta) and kidney transplantation]. 1250 2

Cyclin kinase inhibitor p27(Kip(1)) (p27) has been shown to be upregulated in glomeruli of diabetic animals and mesangial cells cultured under high glucose. This study was an investigation of the role of p27 in the progression of diabetic nephropathy. Mice deficient in p27 (p27 -/-) and wild-type mice (p27 +/+) were studied 12 wk after diabetes induction by streptozotocin. Blood glucose and BP were comparable between diabetic p27 +/+ and p27 -/- mice. The kidney weight to body weight ratio and glomerular volume increased in diabetic p27 +/+ mice. In contrast, these parameters did not change in diabetic p27 -/- mice. Similarly, albuminuria developed in diabetic p27 +/+ mice but not in diabetic p27 -/- mice. The mesangial expansion was significantly milder in diabetic p27 -/- mice than that in diabetic p27 +/+ mice. These changes were associated with a similar increase in glomerular TGF-beta expression in diabetic p27 +/+ and p27 -/- mice. However, glomerular protein expression of fibronectin, a target of TGF-beta, increased only in diabetic p27 +/+ mice. In mesangial cells cultured from p27 +/+ mice, exposure to high glucose caused significant increases in total protein content and [(3)H]-leucine incorporation. On the other hand, high glucose caused a significant reduction in these parameters in cells from p27 -/- mice. Phosphorylation of 4E-BP1, the translation inhibitor, increased after exposure to high glucose in p27 +/+ cells. In p27 -/- cells, the level of phosphorylated 4E-BP1 was higher than that in control p27 +/+ cells and decreased under high glucose conditions. In conclusion, renal hypertrophy, glomerular hypertrophy, and albuminuria did not develop, and mesangial expansion was milder in diabetic p27 -/- mice despite glomerular TGF-beta upregulation. These results suggest that controlling p27 function may ameliorate diabetic nephropathy.
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PMID:The lack of cyclin kinase inhibitor p27(Kip1) ameliorates progression of diabetic nephropathy. 1259 21

Diabetic nephropathy is major long-term complication of diabetes mellitus a social and civilization-related disease. At present, the most sensitive and non-invasive indicator of the progression of diabetic nephropathy is microalbuminuria. Morphological features such as accumulation of extracellular matrix proteins, thickening of glomerules' basement membranes are prior to microalbuminuria. The aim of our clinical study was to establish whether urine and serum TGF-beta 1 and IL-6 levels may be significant in prognosing and evaluating a risk for developing diabetic nephropathy. The trial was carried out in 68 patients with type II diabetes mellitus and a group of 10 healthy subjects served as control. Urine and serum TGF-beta 1 concentrations were evaluated, as well as, basic laboratory parameters. After one-year-observation serum creatinine level and microalbuminuria value were investigated in 60 patients with type II diabetes mellitus. In patients with type II diabetes mellitus both urine and serum TGF-beta 1 and IL-6 were elevated. After one-year-observation of patients with type II diabetes mellitus it was established that the increase of serum creatinine concentrations values were higher in those patients, whose initial TGF-beta 1 levels exceeded normal values. A positive correlation between urine TGF-beta 1 level and the progression of renal failure measured by the increase of serum creatinine level was observed. In conclusion, our findings indicate that urine TGF-beta 1 and IL-6 levels may be a good prognostic factor of the development of diabetic nephropathy in the course of diabetes mellitus.
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PMID:[Cytokines in noninvasive diagnostics of diabetic nephropathy progression]. 1262 78

High-protein diets exacerbate glomerular hyperfiltration and the progression of diabetic nephropathy. The purpose of this study was to determine whether amino acids also produce nonhemodynamic injury in the glomerulus. When rat mesangial cells were cultured with an amino acid mixture designed to replicate the composition in plasma after protein feeding, production of mRNA (Northern blot analysis) and/or protein (ELISA or Western blot analysis) for transforming growth factor-beta1 (TGF-beta1), fibronectin, thrombospondin-1 (TSP-1), and collagen IV were enhanced in a manner comparable to a culture with high glucose (30.5 mM). The bioactive portion of total TGF-beta (NRK assay) increased in response to amino acids. The TSP-1 antagonist LSKL peptide reduced bioactive TGF-beta and fibronectin, indicating the dependence of TGF-beta1 activation on TSP-1. DNA synthesis ([3H]thymidine incorporation), an index of cellular proliferation, increased in response to amino acids and was further enhanced by culture with increased levels of both amino acids and glucose. TGF-beta1 and matrix proteins increased when mesangial cells were cultured with excess l-arginine (2.08 mM) alone. Although l-arginine is the precursor of nitric oxide (NO), such responses to amino acids do not appear to be mediated through increased NO production. NO metabolites decreased in the media, and these responses to mixed amino acids or l-arginine were not prevented by NO synthase inhibition. In conclusion, amino acids induce indicators of response to injury in mesangial cells, even when hemodynamic stress is absent. In conditions associated with increased circulating amino acids, such as diabetes and/or a high-protein diet, direct cellular effects could contribute to glomerular injury.
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PMID:Amino acids induce indicators of response to injury in glomerular mesangial cells. 1264 43

SPARC (Secreted Protein, Acidic and Rich in Cysteine) is a matricellular protein that inhibits mesangial cell proliferation and also affects production of extracellular matrix (ECM) by regulating transforming growth factor-beta1 (TGF-beta1) and type I collagen in mesangial cells. This study is an investigation of the role of SPARC in streptozotocin (STZ)-induced diabetic nephropathy (DN) of 6-mo duration in wild type (WT) and SPARC-null mice. SPARC expression was evaluated by immunohistochemistry (IHC) and by in situ hybridization (ISH). Deposition of type I and IV collagen and laminin was evaluated by IHC, and TGF-beta 1 mRNA was assessed by ISH. Renal function studies revealed no significant difference in BUN between diabetic SPARC-null mice and diabetic WT mice, whereas a significant increase in albumin excretion was detected in diabetic WT relative to diabetic SPARC-null mice. Diabetic WT animals exhibited increased levels of SPARC mRNA and protein in glomerular epithelial cells and in interstitial cells, in comparison with nondiabetic WT mice. Neither SPARC mRNA nor protein was detected in SPARC-null mice. Morphometry revealed a significant increase in the percentage of the glomerular tufts occupied by ECM in diabetic WT compared with nondiabetic WT mice, although there was no difference in the mean glomerular tuft area among groups. In contrast, diabetic SPARC-null mice did not show a significant difference in the percentage of the glomerular tufts occupied by ECM relative to nondiabetic null mice. Tubulointerstitial fibrosis was ameliorated in diabetic SPARC-null mice compared with diabetic WT animals. Further characterization of diabetic SPARC-null mice revealed diminished glomerular deposition of type IV collagen and laminin, and diminished interstitial deposition of type I and type IV collagen correlated with decreases in TGF-beta 1 mRNA compared with WT diabetic mice. These observations suggest that SPARC contributes to glomerulosclerosis and tubulointerstitial damage in response to hyperglycemia through increasing TGF-beta 1 expression in this model of chronic DN.
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PMID:Amelioration of diabetic nephropathy in SPARC-null mice. 1266 Mar 31

Albumin modified by Amadori glucose adducts has been shown to modulate signal transduction and induce alterations in renal glomerular cells that contribute to the development of diabetic nephropathy. However, the participation of this nonenzymatically glycated protein in the pathobiology of atherosclerotic cardiovascular disease in diabetes has not been established. To probe this issue, we used macrophage RAW cells to assess the effects of glycated albumin on molecular events implicated in the pathogenesis of diabetes-related vascular complications. RAW cells were cultured in medium containing 5.5 mmol/L glucose and glycated or nonglycated albumin, with and without the addition of PD98059, a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK), followed by analysis of phosphorylated ERK and the nuclear translocation of nuclear factor (NF)-kappa B and measurement of cellular content of thiobarbituric acid-reactive substances and the concentration of transforming growth factor (TGF)-beta(1) in the spent medium. We demonstrate, for the first time, that glycated albumin activates RAW cell ERK and promotes ERK-dependent increases in TGF-beta(1) production, oxidative stress, and NF-kappa B activation. Preincubation with the antioxidant alpha-lipoic acid partially prevented the glycated albumin-induced increase in NF-kappa B activation. These findings indicate that Amadori-modified glycated albumin modulates macrophage cell biology independent of high glucose concentration. The effects of glycated albumin on RAW cell molecular mediators and cytokine production may have pathophysiologic significance with respect to the accelerated atherosclerosis that occurs in diabetes.
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PMID:Glycated albumin increases oxidative stress, activates NF-kappa B and extracellular signal-regulated kinase (ERK), and stimulates ERK-dependent transforming growth factor-beta 1 production in macrophage RAW cells. 1267 69

While it is thought that advanced glycation end products (AGEs) act by stimulating transforming growth factor (TGF)-beta to mediate diabetic injury, we report that AGEs can activate TGF-beta signaling, Smads, and mediate diabetic scarring directly and independently of TGF-beta. AGEs activate Smad2/3 in renal and vascular cells at 5 min, peaking over 15-30 min before TGF-beta synthesis at 24 h and occurs in TGF-beta receptor I and II mutant cells. This is mediated by RAGE and ERK/p38 mitogen-activated protein kinases (MAPKs). In addition, AGEs also activate Smads at 24 h via the classic TGF-beta-dependent pathway. A substantial inhibition of AGE-induced Smad activation and collagen synthesis by ERK/p38 MAPK inhibitors, but not by TGF-beta blockade, suggests that the MAPK-Smad signaling crosstalk pathway is a key mechanism in diabetic scarring. Prevention of AGE-induced Smad activation and collagen synthesis by overexpression of Smad7 indicates that Smad signaling may play a critical role in diabetic complications. This is further supported by the findings that activation of Smad2/3 in human diabetic nephropathy and vasculopathy is associated with local deposition of AGEs and up-regulation of RAGE. Thus, AGEs act by activating Smad signaling to mediate diabetic complications via both TGF-beta-dependent and -independent pathways, shedding new light on the pathogenesis of diabetic organ injury.
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PMID:Advanced glycation end products activate Smad signaling via TGF-beta-dependent and independent mechanisms: implications for diabetic renal and vascular disease. 1270 99

TSC-22 is a leucine zipper transcriptional factor and expression of the TSC-22 gene is highly induced by TGF-beta treatment. We estimated the frequency of the -396 A/G polymorphism of the TSC-22 gene with an Alu I-Restriction fragment length polymorphism (RFLP) method in 498 Japanese subjects with type 2 diabetes mellitus. We also determined the promoter activity. The diabetic patients with the AA genotype had a significantly higher incidence of the diabetic nephropathy (vs. the AG genotype, P<0.05, odds ratio: 1.95; 95% confidence intervals 1.14-3.33). There was no significant difference in the promoter activity between the fragments with -396A and -396G. These findings suggest that the TSC-22 gene (-396) A allele is associated with an increasing risk of the diabetic nephropathy.
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PMID:The role of the TSC-22 (-396) A/G variant in the development of diabetic nephropathy. 1275 81

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