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)

Albumin modified by Amadori glucose adducts, formed in increased amounts in diabetes, stimulates collagen IV production and gene expression in renal glomerular mesangial cells, and induces mesangial matrix accumulation accompanied by increased mRNA encoding alpha 1 (IV) collagen and fibronectin in diabetic animals. These effects contribute to the pathogenesis of diabetic nephropathy, and resemble biologic activities of the cytokine TGF-beta 1, which also has been causally implicated in diabetic renal disease. We postulated that Amadori-modified glycated albumin modulates TGF-beta 1 expression in mesangial cells, and that TGF-beta 1 participates in mediating the glycated albumin-induced increases in mesangial cell matrix production. To test this hypothesis, we measured mRNA encoding TGF-beta 1, the TGF-beta Type II receptor and fibronectin, a key matrix component of the TGF-beta 1 tissue response, after incubation of mesangial cells with glycated albumin. Steady state levels of the mRNAs encoding for these proteins were stimulated when mesangial cells were cultured in the presence of albumin containing Amadori glucose adducts compared with levels in cells cultured with the nonglycated, glucose-free counterpart. The glycated protein-induced changes in mRNA expression were observed with concentrations of glycated albumin encompassing those found in clinical specimens and in media containing physiologic (5.5 mM) glucose concentrations, indicating that they were due to the glucose-modified protein and not to a hyperglycemic milieu. Further, they were accompanied by increased translated fibronectin protein, which was prevented with TGF-beta neutralizing antibody, as was the glycated albumin-induced increase in fibronectin mRNA. The findings indicate that Amadori-modified glycated albumin stimulates mesangial cell TGF-beta 1 gene expression by mechanisms that are operative under normoglycemic conditions. These data provide the first link between elevated glycated serum albumin concentrations and increased TGF-beta 1 bioactivity in the pathogenesis of mesangial matrix accumulation in diabetes.
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PMID:Glycated albumin stimulates fibronectin gene expression in glomerular mesangial cells: involvement of the transforming growth factor-beta system. 950 8

We investigated the effect of inhibition of a polyol pathway on the glucose-induced increase in transforming growth factor-beta (TGF-beta) production and activity of protein kinase C (PKC) in cultured human mesangial cells (MCs). The exposure of MCs to 33 mmol/l glucose resulted in an increase in TGFbeta production, measured by ELISA, compared with 5 mmol/l glucose. The glucose-induced increase in TGF-beta was prevented by concomitant incubation with epalrestat, an aldose reductase inhibitor (ARI), in a dose-dependent manner at a concentration of more than 10(-6) mol/l. Moreover, the glucose-induced enhancement of PKC activity in the membrane fraction of MCs was also abolished by epalrestat. The addition of epalrestat to MCs cultured with 5 mmol/l glucose showed no demonstrable effects on TGF-beta production and PKC activity. These results provide direct evidence for linkages between derangements in polyol pathway and glucose-induced overproduction of TGF-beta and enhancement of PKC activity in MCs. Accordingly, the effect of an ARI on these metabolic abnormalities in MCs may justify its clinical application for treatment of diabetic nephropathy.
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PMID:An aldose reductase inhibitor prevents glucose-induced increase in transforming growth factor-beta and protein kinase C activity in cultured mesangial cells. 954 Nov 79

The prosclerotic cytokine transforming growth factor beta 1 (TGF-beta1) has been causally implicated in renal pathobiology in diabetes. We sought evidence that the TGF-beta system participates in the nephropathic process in the db/db mouse, a hyperinsulinemic model of genetic diabetes that develops abnormalities in renal morphology and function that parallel those in human diabetic nephropathy. In support of this hypothesis, we found that steady state levels of mRNA encoding the TGF-beta type II receptor were significantly increased in renal cortex from db/db diabetic mice. Additionally, the translated TGF-beta type II receptor protein, assessed by immunoblot, also was increased in diabetic kidneys. However, in contrast to rodents with insulin-deficient diabetes, steady state levels of mRNA encoding TGF-beta1 in the renal cortex of diabetic db/db mice did not differ from those in cortex from nondiabetic (db/m) littermate controls. Further, concentrations of TGF-beta protein, measured by immunoassay and bioassay, were significantly lower in extracts prepared from renal cortex of diabetic animals compared with those from nondiabetic controls. Urine and serum concentrations of immunoreactive TGF-beta1 also were reduced in diabetic mice. The findings are consistent with upregulation of TGF-beta type II receptor activity as a consequence of hyperglycemia in the hyperinsulinemic db/db mouse and suggest that hyperinsulinemia inhibits TGF-beta1 production. The results further suggest that type II receptor upregulation is a contributing factor to the increased gene expression of renal cortical mRNAs encoding the extracellular matrix proteins fibronectin and alpha 1 (IV) collagen and to the renal abnormalities observed in this animal model.
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PMID:The renal TGF-beta system in the db/db mouse model of diabetic nephropathy. 963 38

Nitric oxide (NO) contributes to the alterations in glomerular hemodynamics and extracellular matrix accumulation observed in diabetic nephropathy. High glucose concentrations directly inhibit NO production by rat mesangial cells (RMC). However, the role of peptide growth factors and chemokines in regulating NO synthesis by RMC under normal and high glucose conditions has not been studied. Therefore, we examined the effect of IGF-I, EGF, TGF-beta and RANTES on NO production by RMC maintained in normal (5.6 mM) or high glucose (33.3 mM) for 48 h. No synthesis was determined by measuring nitrite accumulation in conditioned media with the Greiss reaction. In normal glucose media, IGF-I, EGF, and RANTES had no effect on nitrite accumulation while TGF-beta inhibited NO synthesis. In high glucose conditions, IGF-I and EGF significantly enhanced NO production. The effects of RANTES and TGF-beta were unchanged by an elevated glucose concentration. EGF-induced stimulation of NO production in high glucose media was associated with parallel alterations in iNOS gene and protein expression. The modest enhancement in nitrite accumulation provoked by IGF-I in high glucose conditions was not accompanied by demonstrable increases in iNOS mRNA abundance or protein content. In conclusion, peptide growth factors modulate the direct inhibitory effect of high glucose on NO production by cultured mesangial cells. These actions in vivo may limit the adverse consequences of reduced NO production in promoting diabetic nephropathy.
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PMID:High glucose enhances growth factor-stimulated nitric oxide production by cultured rat mesangial cells. 966 75

Our purpose was to elucidate the hypothesis that paracrine-produced transforming growth factor (TGF)-beta1 regulates the accumulation of extracellular matrix (ECM) in renal glomeruli, a hallmark of diabetic nephropathy. To produce TGF-beta1 from the juxtaglomerular apparatus in mouse kidneys, we cloned a mouse Ren-1c promoter fragment (-4.100 to +6 base pairs) upstream of porcine TGF-beta1 (pTGF-beta1) cDNA, mutated to ensure secretion of biologically active TGF-beta beta1. The resulting transgenic mice had significantly more TGF-beta1 in their kidneys than was in those of nontransgenic controls, as confirmed by immunohistochemistry, and the production of TGF-beta1 was enhanced in vivo by captopril-induced stimulation of the Ren-1c promoter. Overproduction of pTGF-beta1 close to the glomerulus resulted in a local accumulation of ECM, composed partly of collagen type IV and laminin, and thickening of the basement membrane, characteristic features of diabetic nephropathy. Interstitial accumulation of ECM and signs of tubular atrophy were present only in older mice (>5 months of age). Results from in situ hybridization and immunohistochemistry suggest that pTGF-beta1 stimulated the production of endogenous TGF-beta1 along collecting ducts and connecting tubules. The increased amount of biologically active TGF-beta1, transgenic as well as endogenous, was corroborated by heightened proteoglycan synthesis from incubated kidney slices. This transgenic model demonstrates that sustained local expression of TGF-beta1 leads to glomerulopathy. We conclude that autocrine- or paracrine-produced TGF-beta1 may play a role in the development of glomerular diseases, such as diabetic nephropathy.
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PMID:Under control of the Ren-1c promoter, locally produced transforming growth factor-beta1 induces accumulation of glomerular extracellular matrix in transgenic mice. 989 41

The small proteoglycan decorin may intercept the activity of the TGF-beta system. Decorin administration has been advocated as potential therapy in renal fibrotic diseases, because of the findings of a relative deficiency of decorin and a relative excess of TGF-beta in acute glomerulonephritis. Does a similar situation pertain in diabetic kidney disease? Activation of TGF-beta seems to be crucial to tissue injury in diabetic nephropathy, but until recently it has not been established whether decorin plays any role in the manifestations of this disease. We review evidence that a surfeit rather than a deficit in decorin expression exists in diabetic renal disease, and that there exists a negative feed-back loop whereby TGF-beta1 induces down-regulation of decorin expression. Rat and mouse mesangial cells as well as mouse proximal tubular cells in culture exhibit increased decorin mRNA levels in high ambient glucose. Decorin mRNA level in the kidney of streptozotocin-induced diabetes in mice is rapidly and significantly increased following the induction of diabetes. Thus, the available evidence suggests that renal decorin is not deficient in this disorder and hence decorin supplementation does not seem to be warranted. Rather, interception of the effects of TGF-beta seems to be an approach most likely to yield beneficial results in diabetic nephropathy.
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PMID:What is the role of decorin in diabetic kidney disease? 1034 40

Nephropathy in patients with type I and II diabetes mellitus is a rapidly increasing problem worldwide. Studies using both glomerular and tubular cells have delineated some of the consequences induced by acute hyperglycemia. In vitro studies have clearly demonstrated that exposure of cultured renal cells, such as glomerular mesangial cells and proximal tubular epithelial cells, to elevated glucose concentrations, may alter cell proliferation and/or extracellular matrix turnover. The latter is effected both directly and indirectly by the alteration of cytokine generation. Furthermore, these in vitro studies have allowed detailed examination of the mechanisms by which exposure of these cells to high ambient glucose concentrations may alter cell function. Extension of these studies to the experimental in vivo situation has confirmed most of the in vitro findings. Important insights gained from models of type I diabetes (i.e. streptocotocin-induced diabetes) as well as type II diabetes (i.e. Goto-Kakizaki (GK) rats and obese Zucker rats) include: (1) The demonstration that increased glomerular cell proliferation and renal matrix accumulation, driven by TGF-beta and/or PDGF, occur in streptocotocin-induced diabetes, yet that nephropathy in these rats does not progress to renal failure. (2) The demonstration that prolonged mild type II diabetes does induce morphological changes characteristic of pre-clinical diabetic nephropathy in GK-rats but does not result in albuminuria or progressive renal disease. (3) The demonstration that the association of type II diabetes with hyperlipidemia in obese Zucker rats results in early podocyte damage and subsequent progression to glomerulosclerosis, tubulointerstitial damage, and renal insufficiency. Identification of the mediators involved in the above processes and in particular of the conditions that will determine progression of subclinical morphological changes to overt nephropathy and renal failure will likely result in future novel therapeutic approaches to diabetic nephropathy.
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PMID:Progression of diabetic nephropathy. Insights from cell culture studies and animal models. 1035 11

Circumstantial evidence from clinical and pathologic correlations in patients with glomerular diseases and proteinuria suggest that glomerular protein ultrafiltration contributes to tubulointerstitial injury. A series of studies was performed to examine the hypothesis that in rats with adriamycin-induced nephropathy or with diabetic nephropathy (but not in normal rats) high molecular wt. growth factors are ultrafiltered into tubular fluid and act on tubular cells through apical membrane receptors. Analysis of proximal tubular fluid that was collected by nephron micropuncture indicates ultrafiltration of IGF-I, TGF-beta and HGF. Respective receptors are also expressed in apical membranes in some parts of the nephron as examined by immunohistochemistry. In vitro cell culture experiments using proximal tubular fluid obtained from rats with experimental glomerular diseases indicate that ultrafiltered IGF-I may contribute to increased distal tubular Na-absorption. Indirect evidence also suggests that this growth factor may increase the secretion of collagen types I and IV in proximal tubular cells. TGF-beta and HGF cause increased expression and basolateral secretion of MCP-1 in proximal tubular and collecting duct cells. There may be other biologic effects on tubules that are caused by apical exposure to ultrafiltered growth factors. These studies suggest that the glomerular ultrafiltration of bioactive proteins causes or contributes to tubulo-interstitial pathology in glomerular proteinuria.
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PMID:Pathophysiologic glomerulotubular growth factor link. 1068 46

Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC beta inhibitor ameliorates not only early diabetes-induced glomerular dysfunction such as glomerular hyperfiltration and albuminuria, but also overexpression of glomerular mRNA for transforming growth factor beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC beta inhibitor on glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC beta inhibitor reduced urinary albumin excretion rates and inhibited glomerular PKC activation in diabetic db/db mice. Administration of a PKC beta inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of glomerular expression of TGF-beta and ECM proteins such as fibronectin and type IV collagen. These findings provide the first in vivo evidence that the long-term inhibition of PKC activation in the renal glomeruli can ameliorate glomerular pathologies in diabetic state, and thus suggest that a PKC beta inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.
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PMID:Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. 1069 58

Diabetic nephropathy is the leading cause of end-stage renal disease in the United States and is a major contributing cause of morbidity and mortality in patients with diabetes. Despite conventional therapy to improve glycemic and blood pressure control the incidence of diabetic nephropathy is reaching epidemic proportions worldwide. As the major pathologic feature of diabetic nephropathy is diffuse mesangial matrix expansion, the pro-sclerotic cytokine transforming growth factor-beta, TGF-beta, is a leading candidate to mediate the progression of the disease. Numerous studies have now demonstrated that TGF-beta is a key factor in experimental models of diabetic kidney disease as well as in patients with diabetic nephropathy. Recent studies have begun to explore the mechanisms by which TGF-beta is stimulated by high glucose and how TGF-beta exerts its matrix-stimulating effects on renal cells. TGF-beta may also be involved in mediating the vascular dysfunction of diabetic kidney disease via its effects on the key intracellular calcium channel, the inositol trisphosphate receptor (IP(3)R). As there is substantial evidence for a cause and effect relationship between upregulation of TGF-beta and the progression of diabetic kidney disease, future studies will seek to establish specific targets along these pathways at which to intervene.
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PMID:TGF-beta in diabetic kidney disease: role of novel signaling pathways. 1070 59


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