Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mesangial cells are responsible for the synthesis of mesangial matrix as well as its degradation, which is mediated by a number of proteolytic activities, including metalloproteinases (MMPs). Imbalanced matrix protein metabolism may be responsible for mesangial expansion and glomerulosclerosis in diabetic nephropathy. Heparin prevents this complication. In human and murine mesangial cell cultures, RT-PCR was able to detect mRNA expression for a number of molecules involved in the mesangial extracellular matrix turnover: type IV collagen [alpha 1(IV)COLL], MMP-1, MMP-2, MMP-3, MMP-9 and MMP-10, and the tissue inhibitors TIMP-1 and TIMP-2. The expression of mRNA for alpha 1(IV)COLL and MMP-2/TIMP-2 balance was studied in human cells in the presence of high glucose and heparin. mRNAs for all the studied molecules were expressed at different levels. Interestingly, a shift in the balance of alpha 1(IV)COLL, MMP-2 and TIMP-2 was observed in high glucose, which was partially reversed by heparin supplementation. The new equilibrium was mostly due to the down-regulation of type IV collagen expression, rather than further reduction of potential proteolysis. Our data, while extending the list of potential mediators of mesangial matrix catabolism, highlight a molecular mechanism by which the pathogenesis of diabetic nephropathy may be sustained, and at the same time suggest that heparin may have the potential to correct this abnormality.
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PMID:Effect of glucose and heparin on mesangial alpha 1(IV)COLL and MMP-2/TIMP-2 mRNA expression. 907 22

Accumulation of mesangial matrix in diabetic nephropathy is caused by increased synthesis and decreased degradation. We have previously demonstrated that incubation in high-glucose medium decreases mesangial cell collagenase activity (Diabetes 44:929-935, 1995). Because angiotensin II (AII) is involved in the pathogenesis of diabetic nephropathy, the present studies were performed to determine if AII mediates glucose-induced 1) inhibition of mesangial collagenase activity, 2) mesangial matrix accumulation, and 3) in-crease in transforming growth factor (TGF)-beta1 secretion in mesangial cells. The direct effect of high glucose on AII generation in mesangial cells was also determined. Primary mesangial cells from normal Sprague-Dawley rats were used in all studies. Collagenase activity in cell medium was determined using three methods: 1) zymography; 2) quantitative assay using fluoresceinated gelatin as substrate; and 3) a new enzyme-linked immunosorbent assay (ELISA) that specifically measures 72-kDa collagenase (MMP-2), the principal collagenase synthesized by mesangial cells. Matrix accumulation was estimated by immunoperoxidase assay on cell layers using anti-glomerular basement membrane (GBM) antibodies. TGF-beta1 and AII levels were determined by ELISA. Exposure of mesangial cells to 30 mmol/l glucose (high glucose) vs. 5 mmol/glucose (normal glucose) for 5 days resulted in a significant decrease in collagenase activity (25%) that was normalized by 10(-4) mol/l losartan, a type 1 angiotensin II (AT1) receptor antagonist. High glucose increased anti-GBM binding compared with normal glucose; this effect of glucose was reversed by losartan. Incubation of cells with 30 mmol/l glucose increased total TGF-beta1 secretion, which was also normalized by losartan. Addition of AII (10(-6) mol/l) for 24 h to the culture medium inhibited collagenase activity by 33%; losartan (10(-4) mol/l) blocked this inhibition of enzyme activity. Also, AII decreased collagenase (MMP-2) levels but stimulated TGF-beta1 secretion in mesangial cells. Finally, glucose increased mesangial AII generation in a concentration-dependent manner, with incubation in 30 mmol/l glucose increasing AII by 25% compared with 5 mmol/l glucose. We conclude that glucose increases AII production by mesangial cells, which results in stimulation of TGF-beta1 secretion, decreased matrix degradation, and increased matrix accumulation. These effects of AII are mediated by the AT1 receptor.
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PMID:Role of angiotensin II in glucose-induced inhibition of mesangial matrix degradation. 1051 75

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the extracellular matrix (ECM). The membrane-type matrix metalloproteinases (MT-MMPs) are a new family of MMPs that differ from other MMPs in that they have a transmembrane domain that anchors them to the cell surface. MT-MMPs have been shown to function as receptors and activators for other MMPs and to localize extracellular matrix proteolysis at the pericellular region. Here we report on mRNA and protein expression of the fifth human MT-MMP (MT5-MMP), a 64-kDa protein that is capable of converting pro-MMP-2 to its active form, in human kidney as well as its upregulation in diabetes. We also demonstrate upregulation of the active form of MMP-2 in kidney samples from patients with diabetes. Through immunohistochemistry, MT5-MMP expression was localized to the epithelial cells of the proximal and distal tubules, the collecting duct, and the loop of Henle. Furthermore, the tubular epithelial cells that expressed MT5-MMP were associated with tubular atrophy. Because renal tubular atrophy is a significant factor in the pathogenesis of diabetic nephropathy and renal failure and the molecular mechanisms regulating this process remain unknown, it is hypothesized that the elevated expression of MT5-MMP contributes to the activation of pro-MMP-2, which participates in the remodeling of the proximal and distal tubules as well as in the collecting duct. These results provide the first evidence of the expression of a MT-MMP in diabetes and suggest a novel role for MT5-MMP in the pathogenesis of renal tubular atrophy and end-stage renal disease.
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PMID:Upregulated expression of human membrane type-5 matrix metalloproteinase in kidneys from diabetic patients. 1145 23

Thickening of the tubular basement membrane (TBM) occurs in diabetic nephropathy, but the effects of high glucose on the functional aspects of proximal tubular epithelial cells are not clearly understood. In the present study, we examined the effects of elevated glucose concentrations on (a) integrin expression by human proximal tubular epithelial cells (HK-2) and integrin-mediated interactions with type IV collagen (colIV) and laminin, major components of TBM; (b) the expression of matrixins/matrix metalloproteinases (MMPs), which is regulated by integrins; and (c) the expression of tissue inhibitors of metalloproteinases (TIMPs). HK-2 cells cultured in 25 mM glucose underwent a reduction of the expression of alpha3, beta1, alpha(v)beta3, and alpha5 integrin subunits, with a concomitant increase of the alpha2 subunit, compared with cells grown in 5 mM glucose. Adhesion experiments demonstrated that high glucose led to increased cell adhesion on either colIV or laminin. Experiments of competition of adhesion using anti-integrin antibodies indicated that HK-2 cells in 5 mM glucose used mainly alpha(v)beta3 and alpha5beta1 integrins to adhere to colIV, whereas in 25 mM glucose they additionally used alpha2beta1. In the case of laminin, a beta1-mediated adhesion was observed when HK-2 cells were in 5 mM glucose, whereas in 25 mM glucose, alpha2beta1 and alpha(v)beta3 were also involved. Elevated glucose concentrations resulted in decreased expression of MMP-9 and MMP-2, whereas an increase in TIMP-1 and a decrease in TIMP-2 expression were observed. We also examined which integrins mediated the expression and secretion of matrixins MMP-2 and MMP-9. Ligation of alpha3beta1 with mAbs resulted in induction of MMP-2 expression and secretion, whereas antibody ligation of alpha(v)beta3 led to down-regulation of MMP-9. The above data implicate integrins of proximal tubular epithelial cells in the regulation of MMPs and in the development of TBM thickening in diabetic nephropathy.
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PMID:Proximal tubular epithelial cell integrins respond to high glucose by altered cell-matrix interactions and differentially regulate matrixin expression. 1217 47

The alterations in the microvascular system of diabetes mellitus patients are responsible for the most devastating complications of this widespread disease. In the kidney, the microangiopathy leads to thickening of the glomerular capillary basement membrane but also to the expansion of the mesangial matrix and thickening of the tubular basement membrane. Several mechanisms are implicated in the pathogenesis of diabetic renal microangiopathy. These include increased synthesis of type IV collagen following hyperglycaemia-induced alteration of the pattern of podocyte-integrin expression, decreased expression of matrix metalloproteinases (MMP-2 and 3), and increased expression of tissue inhibitor of metalloproteinase (TIMP). An altered morphology of podocytes accompanies these basement membrane alterations. Other factors which may contribute to renal matrix accumulation include vascular endothelial growth factor (VEGF), since treatment with anti-VEGF antibodies attenuates glomerular basement membrane thickening, platelet-derived growth factor (PDGF) (B chain) and its receptor, which appear to be highly expressed in mesangial and visceral epithelial cells and might play a role in the development of diabetic nephropathy. Also oxygen radicals/oxidative stress may play a role in matrix accumulation in diabetic nephropathy as aminoguanidine, an inhibitor of the formation of advanced glycation end-products but with antioxidant properties, attenuates diabetic nephropathy. Retinal diabetic microangiopathy follows much the same principles, be it that microvascular proliferation is a distinctive element in the retina. Nephropathy and retinopathy occur frequently but not always together, indicating that in their multifactorial pathogenesis much remains to be clarified.
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PMID:Microvascular basement membranes in diabetes mellitus. 1284 21

Diabetic nephropathy is related to glomerular extracellular matrix (ECM) accumulation that leads to glomerulosclerosis. Fluvastatin as a lipid-lowering medicine significantly prevents diabetic nephropathy, probably not only through its lipid-lowering action, but also mainly through its direct suppression of glomerular ECM accumulation. To test this hypothesis, in the present study, a five-sixths nephrectomized (5/6Nx) rat model to induce a renal ECM accumulation without coexistence of hyperlipidemia was used to investigate the effect of fluvastatin on renal function, glomerular ECM accumulation and expression of connective tissue growth factor (CTGF). 5/6Nx induced a significant nephropathy in rats at 13 weeks, indicated by renal dysfunction including increases in blood urine nitrogen, creatinine and urinary protein excretion, and renal histopathological changes. Administration of fluvastatin significantly prevented the renal dysfunction and histological abnormalities in the 5/6Nx rats. Furthermore, both significant suppression of matrix metalloproteinases (MMPs) activity such as MMP-2 and significant activation of tissue inhibitors of MMP (TIMPs) such as TIMP-2 observed in the 5/6Nx rats were almost completely prevented by fluvastatin, resulting in a significant prevention of glomerular ECM accumulation. For upstream mediator of ECM accumulation, 5/6Nx significantly up-regulated CTGF mRNA expression, but fluvastatin treatment prevented CTGF up-regulation. These results suggest that fluvastatin, as one of well-known lipid-lowering agents, plays an important role in the prevention of nephropathy, likely through suppression of CTGF-mediated ECM accumulation. Therefore, fluvastatin may be a potential candidate for developing a pharmaceutical approach to the prevention of diabetic nephropathy due to its both lipid-lowering and direct anti-renal ECM accumulation actions.
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PMID:Fluvastatin prevents nephropathy likely through suppression of connective tissue growth factor-mediated extracellular matrix accumulation. 1473 71

High glucose concentration inhibits matrix degradation and affects the activities of the enzymes responsible, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Connective tissue growth factor (CTGF) expression is increased in diabetic nephropathy and is a downstream mediator of TGF-beta actions. However, whether CTGF regulates matrix degradation and the mechanism of effect in diabetes has not been reported. Human mesangial cells were cultured in media containing 5 or 25 mM glucose and, in some experiments, with recombinant human (rh)CTGF (0-1000 ng/ml) and/or appropriate neutralizing antibodies. Matrix degradation was inhibited by rhCTGF in a dose-dependent manner, and the decrease in matrix degradation caused by high glucose and by TGF-beta was significantly attenuated by addition of CTGF-neutralizing antibody (by 40.2 and 69.1%, respectively). Similar to 25 mM glucose, addition of rhCTGF increased MMP-2, TIMP-1, and TIMP-3 mRNA by 2.5-, 2.1-, and 1.6-fold, respectively (P < 0.05) but had no effect on membrane-type (MT)1-MMP or TIMP-2. Addition of TIMP-1 antibody to conditioned medium abolished the decrease in degradation caused by rhCTGF and partially prevented (by 79%) the glucose-induced inhibition of matrix degradation. In vivo studies of glomeruli from diabetic and control rats showed that intensive insulin treatment prevented the increase in expression of CTGF and TIMP-1 and attenuated the decreased matrix degradation seen in diabetes. In summary, CTGF inhibits matrix degradation by increasing TIMP-1 expression, and by this action it contributes to the inhibition of matrix breakdown by high glucose, implying that CTGF has a role in the reduced matrix degradation observed in diabetic nephropathy.
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PMID:Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1: implications for diabetic nephropathy. 1534 71

Diabetic nephropathy (DN) is a common complication of diabetes types 1 and 2. One of the hallmarks of DN is the development of mesangial expansion, which occurs through accumulation of extracellular matrix (ECM) components. Altered local gene expression of humoral factors (eg, transforming growth factor-b, connective tissue growth factor, and platelet-derived growth factor) can lead to increased production of ECM components (eg, fibronectin and collagen IV) or decreased degradation through matrix metalloproteinases (eg, MMP-1, MMP-2). In recent years, new techniques for examination of gene expression have been developed. Because of their large scale and high-throughput character, it is now possible to examine differential gene expression in a large number of samples. This paper provides an overview of techniques used and results obtained in studies of DN. Newly developed concepts of how altered gene expression may affect histomorphologic features or clinical symptoms are also discussed.
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PMID:Gene expression in diabetic nephropathy. 1553 12

Diabetic nephropathy is characterized by excessive accumulation of extracellular matrix (ECM) in the kidney. Decreased ECM degradation as well as increased ECM synthesis plays an important role in ECM remodeling that favours tissue fibrosis. Plasminogen activator (PA)/plasmin/PA inhibitor (PAI) system is involved in ECM degradation and PAI-1 plays a critical role in ECM remodeling in the kidney. Normal human kidneys do not express PAI-1 but PAI-1 is overexpressed in pathologic conditions associated with renal fibrosis including diabetic nephropathy. Reactive oxygen species mediate PAI-1 up-regulation in renal cells cultured under high glucose, hypoxia, and TGF-beta1. Recent studies utilizing PAI-1 deficient mice suggest that PAI-1 induce ECM deposition in diabetic kidney through increased ECM synthesis by TGF-beta1 up-regulation as well as through decreased ECM degradation by suppression of plasmin and MMP-2 activity.
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PMID:Plasminogen activator inhibitor-1 and diabetic nephropathy. 1617 79

Recent evidences have demonstrated an important role for glomerular visceral epithelial cell (podocyte) in the development and progression of diabetic nephropathy. We investigated the high-glucose (HG)-triggered signaling pathway and its role in matrix metalloproteinase (MMP) production in murine podocytes. The activity of 92-kDa (MMP-9) gelatinase, but not of 72 kDa (MMP-2), in an HG medium significantly increased during incubation of 2 to 3 days and decreased during incubation of more than 5 days revealed by Gelatin zymography. Opposite to the increases in MMP-9 activity, HG medium produced significant decreases in the protein levels of alpha5(IV) collagen. Changes in MMP-9 activity were associated with the same pattern as MMP-9 mRNA levels in podocytes exposed to HG media. HG medium rapidly activated ERK1/2 MAPK in podocytes. Moreover, ERK1/2 activation was required for HG-induced enhancement of MMP-9 activity and a decrease in the level of alpha5(IV) collagen. HG incubation rapidly induced an increase in the nuclear accumulation of Ets-1 protein. Blocking the ERK pathway suppressed HG-induced expression and nuclear accumulation of transcriptional factor Ets-1, and MMP-9 mRNA expression. We suggest that short- or long-term exposure to HG concentrations increases or decreases MMP-9 production and alpha5(IV) collagen expression in podocytes, this may contribute to the GBM abnormality caused by an imbalance in extracellular matrix (ECM) synthesis and degradation, and may play a critical role in the pathogenesis of proteinuria in diabetic nephropathy.
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PMID:High ambient glucose levels modulates the production of MMP-9 and alpha5(IV) collagen by cultured podocytes. 1654 22


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