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

A large number of experimental studies in animals and retrospective or non-randomised prospective studies in humans provide support for the concept that the microvascular complications of diabetes mellitus are dependent on hyperglycaemia. This review focuses on four potential biochemical pathways linking hyperglycaemia to changes within the kidney which can plausibly be linked to the functional and structural changes characterising diabetic nephropathy. These four pathways are the polyol pathway, non-enzymatic glycation, glucose autoxidation and de novo synthesis of diacylglycerol leading to protein kinase C and phospholipase A2 activation. Rather than being independent, there are several potential interactions between these four pathways which may explain confusing and overlapping effects observed in studies examining inhibitors of individual pathways. As many of the steps which follow on glucose metabolism are subject to modification by dietary and pharmacological means, the further delineation of the pathogenetic sequence leading to tissue damage in diabetes should allow a logical and effective approach to the prevention or treatment of the complications of diabetes.
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PMID:The link between hyperglycaemia and diabetic nephropathy. 161 21

Renal injury in diabetes mellitus is a major cause of morbidity and mortality in diabetic patients. There is a clear correlation between the degree of glomerular as well as tubulointerstitial lesions and the development of reduced glomerular filtration rate. The important role of hyperglycemia in the genesis of diabetic renal disease has been strengthened by the application of tissue culture techniques. Recent in vitro studies, first in tubular epithelial cells and subsequently in the three glomerular cell types, have provided supportive evidence that high ambient glucose per se stimulates the synthesis of extracellular matrix components. Increased matrix synthesis and decreased degradation are thought to contribute to matrix accumulation in diabetic nephropathy. These processes are not mutually exclusive and they may be operating simultaneously but at different rates, with increased synthesis predominating early and decreased breakdown later in the course of the disease. Likely mediators of the effects of high glucose involve activation of the polyol pathway, altered myo-inositol metabolism, increased protein kinase C activity, and/or nonenzymatic glycation of various matrix proteins. A role for various growth factors, especially transforming growth factor-beta, also seems likely. However, the details of the cell-signaling mechanisms and the putative molecular mediators of the effect of hyperglycemia remain to be firmly established.
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PMID:Mediators of hyperglycemia and the pathogenesis of matrix accumulation in diabetic renal disease. 756 78

The metalion vanadate has insulin-like effects and has been advocated for use in humans as a therapeutic modality for diabetes mellitus. However, since vanadate is a tyrosine phosphatase inhibitor, it may result in undesirable activation of target cells. We studied the effect of vanadate on human mesangial cells, an important target in diabetic nephropathy. Vanadate stimulated DNA synthesis and PDGF B chain gene expression. Vanadate also inhibited total tyrosine phosphatase activity and stimulated tyrosine phosphorylation of a set of cellular proteins. Two chemically and mechanistically dissimilar tyrosine kinase inhibitors, genistein and herbimycin A, blocked DNA synthesis induced by vanadate. Vanadate also stimulated phospholipase C and protein kinase C. Downregulation of protein kinase C abolished vanadate-induced DNA synthesis. Thus, vanadate-induced mitogenesis is dependent on tyrosine kinases and protein kinase C activation. The most likely mechanism for the effect of vanadate on these diverse processes involves the inhibition of cellular phosphotyrosine phosphatases. These studies demonstrating that vanadate activates mesangial cells may have major implications for the therapeutic potential of vanadate administration in diabetes. Although vanadate exerts beneficial insulin-like effects and potentiates the effect of insulin in sensitive tissue, it may result in undesirable activation of other target cells, such as mesangial cells.
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PMID:Activation of mesangial cells by the phosphatase inhibitor vanadate. Potential implications for diabetic nephropathy. 788 73

Mesangium enlargement is a constant feature of diabetic nephropathy and is likely to be important in the pathogenesis of this diabetic complication. Whether decreased degradation of mesangium plays any role in causing the enlargement is uncertain. We developed a system of preparing radioactively labeled mesangium matrix from mesangial cell cultures to be used as substrates for studies of mesangium degradation. Degradation is commenced by growing mesangial cells on the labeled matrix and monitored by the release of radioactivity into the culture medium. High glucose concentration (30 mM), whether present 1) when the matrix is being made or 2) when the degradation is taking place, reduces the rate of mesangium degradation. The second but not the first of these two phenomena was abolished by aminoguanidine. Phorbol 12-myristate 13-acetate, added in a manner to antagonize the action of protein kinase C, inhibited mesangium degradation and was not able to nullify the effect of high glucose. Thus it appears unlikely that a high glucose concentration inhibits mesangium degradation by increasing mesangial cell protein kinase C activity. We conclude that decreased degradation of mesangium as a result of hyperglycemia may play a role in causing the mesangium enlargement that occurs in diabetic nephropathy.
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PMID:High glucose concentration causes a decrease in mesangium degradation. A factor in the pathogenesis of diabetic nephropathy. 803 98

Diabetes mellitus alters the cellular production of eicosanoids in a number of tissues, including the kidney, and these agents have in turn been implicated in the pathogenesis of diabetic nephropathy. As delineated in the streptozotocin diabetic rat (SDR) model, a preferential enhancement of glomerular synthesis of the vasodilatory prostaglandins (PGs) PGE2 and PGI2 with concurrent smaller increases in thromboxane (TX)A2 occurs within 1 week after induction of diabetes. This early alteration in glomerular synthesis of eicosanoids in the SDR has been linked to glucose-induced activation of the glomerular protein kinase C signalling system that enhances phospholipase A2 activity and, therefore, release of membrane-bound arachidonic acid for oxygenation. The preferential increase in glomerular production of vasodilatory PGs may contribute to the glomerular hyperfiltration that is characteristic of early diabetes. After more prolonged (months) diabetes in the SDR, glomerular generation and urinary excretion of thromboxane (TX) are preferentially enhanced. Studies with selective inhibitors of TX synthesis in the SDR have implicated this eicosanoid in the pathogenesis of both albuminuria and glomerular structural changes (basement membrane thickening and mesangial matrix expansion). Direct stimulation of matrix protein production has been demonstrated in cultured mesangial cells in response to both TX and high ambient concentrations of glucose. The actions of TX and glucose on mesangial cell matrix production appear to be interactive, with each signalled through distinct pathways of protein kinase C activation.
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PMID:Eicosanoids in the pathogenesis of the functional and structural alterations of the kidney in diabetes. 823 21

Impaired heparan sulphate biosynthesis through diabetes-induced inhibition of glucosaminyl N-deacetylase may have a central role in the development of diabetic nephropathy, and genetic differences in the vulnerability of the N-deacetylase could influence the risk of developing nephropathy. We studied N-deacetylase activity in fibroblast cultures from Type 1 (insulin-dependent) diabetic patients with (n = 14) or without (n = 13) diabetic nephropathy, together with non-diabetic control subjects (n = 7). No difference in N-deacetylase activity was found (p = 0.13), and no inhibition of N-deacetylase was found in cultures grown at 25 mmol/l glucose. N-deacetylase activity was inversely correlated to growth rate (r = -0.59, p = 0.0008), and in patients with nephropathy a negative correlation between HbA1C and fibroblast N-deacetylase activity (r = -0.72, p = 0.012) was found. Cell-cycle analysis revealed an increased fraction of S-phase cells in patients with nephropathy (28%(21-52%)) compared to healthy control subjects (17% (9-24%)), p = 0.0008, but not between patients with and without nephropathy (latter group 26%(11-43%)), p = 0.43. Forskolin, an activator of protein kinase A, specifically decreased N-deacetylase activity, whereas activation of protein kinase C produced a combined reduction in N-deacetylase activity and total protein synthesis. In conclusion, no constitutive defects in N-deacetylase activity were found in fibroblasts from these patients. Further studies should consider possible associations between fibroblast characteristics and pre-biopsy environmental parameters related to cellular memory phenomena. Finally, activation of protein kinase A provides a potential general pathway for regulating N-deacetylase activity.
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PMID:Glucosaminyl N-deacetylase in cultured fibroblasts; comparison of patients with and without diabetic nephropathy, and identification of a possible mechanism for diabetes-induced N-deacetylase inhibition. 833 76

Like the renal glomerular mesangium in patients with diabetic nephropathy, glomerular mesangial cell cultures grown in 30 mM glucose accumulate increased amounts of the extracellular matrix (ECM) proteins fibronectin, laminin, and type IV collagen. This is due to increased ECM protein synthesis and mRNA levels. Similar to other cells types that are affected by the diabetic state (such as, vascular cells and peripheral nerve), mesangial cells transport glucose by an insulin-independent, facilitated diffusion transport system. Kinetic studies reveal that intracellular glucose levels may reach the ambient glucose concentrations achieved in diabetes. Growth studies reveal that glucose does not exert its effect on mesangial cell ECM accumulation by affecting cell growth, but rather it causes an increase in diacylglycerol (DAG) mass and activates protein kinase C. Agents such as phorbol myristate acetate (PMA) and the cell permeable DAG analogue, oleoyl acetyl glycerol (OAG) which activate protein kinase C also increase ECM mRNAs. These results implicate protein kinase C activation in the increased ECM accumulation observed in mesangial cell cultures grown in high glucose.
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PMID:The glomerular mesangium in diabetes mellitus. 843 49

Diabetic late complications are characterized by morphological and biochemical alterations of the extracellular matrix. In particular, longstanding diabetes causes quantitative and qualitative changes in basement membrane structure of retinal and renal capillaries. Immunohistochemical investigations of diabetic kidneys with diffuse glomerulosclerosis show increased collagen type IV deposition in the mesangial matrix and decreased heparan sulfate proteoglycan content in the mesangial matrix and glomerular basement membrane as well. In nodular glomerulosclerosis normal basement membrane components are decreased or absent while the occurrence of collagen type III in this stage has been interpreted as an irreversible alteration of the glomerular structure. These changes seem to be the underlying cause for the alterations in renal functions like persistent albuminuria and proteinuria. Increased intra- and extracellular levels of glucose and its derivatives are thought to be responsible for diabetic tissue dysfunction although there are reports on possible genetic defects causing increased susceptibility to develop diabetic nephropathy. Recent results, however, focus on the role of glucose-induced cytokine secretion as mediator for altered metabolism of glomerular matrix proteins. In vitro studies with cultured kidney cells have shown that the glucose-induced dysregulation of the basement membrane synthesis may be mediated by a glucose dependent activation of protein kinase C. Alternatively or synergistically, the formation of AGE products formed after prolonged exposure of matrix proteins to elevated glucose may also lead to cytokine secretion subsequently inducing synthesis of extracellular matrix proteins. Studies in experimental animals confirm the diabetes induced dysregulation of the synthesis of extracellular matrix components on the molecular level.
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PMID:Alterations of glomerular matrix proteins in the pathogenesis of diabetic nephropathy. 851 35

Increased Na+/H+ exchanger (NHE) activity has been demonstrated in cells from patients with hypertension and diabetic nephropathy. Vascular myocytes from the spontaneously hypertensive rat (SHR) also exhibit increased NHE activity as compared with cells from the normotensive Wistar Kyoto rat (WKY). The interaction of increased glucose concentrations with NHE activity is unclear. The effect of glucose on NHE activity, NHE-1 (isoform 1) protein expression, and phosphorylation of cultured vascular myocytes from these rat strains was thus investigated. NHE activity was determined fluorometrically with 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF). A rabbit NHE-1-specific polyclonal antibody was used (1) to measure NHE-1 abundance in Western blots of cell extracts and (2) for immunoprecipitating 32P-labeled NHE-1. Cells from SHR exhibited increased NHE activity and NHE-1 phosphorylation as compared with cells from WKY, with similar NHE-1 protein content per cell. Incubation in 25 mmol.L-1 glucose for 24 hours led to increased NHE activity only in WKY cultures, with no change in NHE-1 protein but a concomitantly reduced NHE-1 phosphorylation. Changes in NHE activity in WKY cells were reversed by inhibition of protein kinase C. Incubation of SHR cells with 25 mmol.L-1 glucose did not enhance the increased NHE activity or NHE-1 phosphorylation present in these cells. Thus, high glucose levels have disparate effects on NHE activity and NHE-1 phosphorylation in cells from different rat strains. The glucose-induced increase in NHE-1 turnover number in WKY cells is not mediated by an increase in its direct phosphorylation, but is dependent on protein kinase C.
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PMID:Glucose-induced changes in activity and phosphorylation of the Na+/H+ exchanger, NHE-1, in vascular myocytes from Wistar-Kyoto and spontaneously hypertensive rats. 854 67

Diabetic nephropathy is characterized by glomerular basement membrane thickening and mesangial expansion. Immunohistochemical studies of diabetic kidneys showed an increased collagen type IV synthesis and deposition in the mesangial matrix, while the glomerular heparan sulfate proteoglycan content was decreased. In nodular glomerulosclerosis massive deposition of collagens III and VI appears, possibly indicating irreversibility of the pathological process. These structural changes seem to be the underlying cause for the alterations of renal functions like persistent albuminuria and proteinura. In a recent study significant glomerular infiltration by macrophages at all stages of glomerulosclerosis was observed. The pathogenesis of the multitude of cellular, structural, and functional abnormalities in diabetic nephropathy is likely to be multifactorial, involving chronic hyperglycemia as well as genetic determinants. In vitro studies with cultured glomerular cells have indicated that hyperglycemia induces transforming growth factor beta, a matrix-producing cytokine. The hyperglycemia-induced cytokine production may involve protein kinase C activation and/or the formation of advanced glucosylation end products. The elucidation of the pathogenesis of diabetic nephropathy may suggest new ways for therapeutic interventions.
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PMID:Structural and functional changes in diabetic glomerulopathy. 895 43


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