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)

Accumulation of mesangial matrix is a pivotal event in the pathophysiology of diabetic nephropathy. The molecular triggers for matrix production are still being defined. Here, suppression subtractive hybridization identified 15 genes differentially induced when primary human mesangial cells are exposed to high glucose (30 mM versus 5 mM) in vitro. These genes included (a) known regulators of mesangial cell activation in diabetic nephropathy (fibronectin, caldesmon, thrombospondin, and plasminogen activator inhibitor-1), (b) novel genes, and (c) known genes whose induction by high glucose has not been reported. Prominent among the latter were genes encoding cytoskeleton-associated proteins and connective tissue growth factor (CTGF), a modulator of fibroblast matrix production. In parallel experiments, elevated CTGF mRNA levels were demonstrated in glomeruli of rats with streptozotocin-induced diabetic nephropathy. Mannitol provoked less mesangial cell CTGF expression in vitro than high glucose, excluding hyperosmolality as the key stimulus. The addition of recombinant CTGF to cultured mesangial cells enhanced expression of extracellular matrix proteins. High glucose stimulated expression of transforming growth factor beta1 (TGF-beta1), and addition of TGF-beta1 to mesangial cells triggered CTGF expression. CTGF expression induced by high glucose was partially suppressed by anti-TGF-beta1 antibody and by the protein kinase C inhibitor GF 109203X. Together, these data suggest that 1) high glucose stimulates mesangial CTGF expression by TGFbeta1-dependent and protein kinase C dependent pathways, and 2) CTGF may be a mediator of TGFbeta1-driven matrix production within a diabetic milieu.
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PMID:Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. 1002 5

We characterized a rabbit polyclonal antibody raised against human recombinant connective tissue growth factor (CTGF). The antibody recognised a higher molecular mass form (approx. 56 kDa) of CTGF in mesangial cell lysates as well as the monomeric (36-38 kDa) and lower molecular mass forms (<30 kDa) reported previously. Immunohistochemistry detected CTGF protein in glomeruli of kidneys of non-obese diabetic mice 14 days after the onset of diabetes, and this was prominent by 70 days. CTGF protein is also present in glomeruli of human patients with diabetic nephropathy. No CTGF was detected in either normal murine or human glomeruli. Transient transfection of a transformed human mesangial cell line with a CTGF-V5 epitope fusion protein markedly increased fibronectin and plasminogen activator inhibitor-1 synthesis in cultures maintained in normal glucose (4 mM) conditions; a CTGF-antisense construct reduced the elevated synthesis of these proteins in high glucose (30 mM) cultures. Culture of primary human mesangial cells for 14 days in high glucose, or in low glucose supplemented with recombinant CTGF or transforming growth factor beta1, markedly increased CTGF mRNA levels and fibronectin synthesis. However, whilst co-culture with a CTGF-antisense oligonucleotide reduced the CTGF mRNA pool by greater than 90% in high glucose, it only partially reduced fibronectin mRNA levels and synthesis. A chick anti-CTGF neutralizing antibody had a similar effect on fibronectin synthesis. Thus both CTGF and CTGF-independent pathways mediate increased fibronectin synthesis in high glucose. Nevertheless CTGF expression in diabetic kidneys is likely to be a key event in the development of glomerulosclerosis by affecting both matrix synthesis and, potentially through plasminogen activator inhibitor-1, its turnover.
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PMID:Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. 1156 71

Although considerable improvement in the prognosis of diabetic nephropathy has been achieved in recent years due to intensive insulin and angiotensin-converting enzyme inhibitor treatment, these approaches do not provide complete protection against progression of diabetic nephropathy. An urgent need for additional novel therapies to prevent or further slow the progression of diabetic nephropathy motivated us to provide an up-to-date review with particular emphasis on the potential role of two growth factors--transforming growth factor-beta and connective tissue growth factor--in the pathogenesis of diabetic nephropathy. The most intensively studied to date, transforming growth factor-beta appears to play a central role in the pathogenesis of diabetic nephropathy. Recently, attention has focused on connective tissue growth factor, which mimics the biological activity of transforming growth factor-beta in profibrotic tissue formation. Thus, acting as a downstream mediator of the profibrotic activity of transforming growth factor-beta, connective tissue growth factor may constitute a more specific target for future antifibrotic therapies.
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PMID:Pathogenesis of diabetic nephropathy: focus on transforming growth factor-beta and connective tissue growth factor. 1170 99

A number of novel genes that are up-regulated in diabetic kidneys have been identified. Recently, transforming growth factor-beta (TGF-beta)--driven secreted proteins, i.e., connective tissue growth factor (CTGF) and gremlin, were identified. They are up-regulated in kidneys of diabetic animals and modulate the biology of mesangial cells. CTGF mediates TGF-beta--induced matrix overproduction by the mesangial cells. Gremlin is a putative antagonist of bone morphogenetic protein-2 that blocks mesangial cell proliferation. Thus, gremlin may modulate the biology of mesangium by stimulating mesangial cell proliferation and in turn production of matrix. In addition, transcriptionally regulated kinases, serum glucocorticoid-regulated kinase and munc-13 have been identified. The former stimulates renal tubular Na+ transport and is involved in hyperfiltraion of diabetic kidneys by a Na+ transport feedback mechanism. Munc-13 has been shown to induce apoptosis in hyperglycemic state via diacylglycerol-activated, PKC-independent signaling pathway. Another pathway relevant to diabetic nephropathy is polyol pathway, where glucose is reduced to sorbitol by aldose reductase. Recently, a renal-specific reductase of the aldo-keto reductase family was isolated. It is up-regulated in diabetic mice, and this could serve as a suitable target for gene therapy in renal complications of diabetes. Several mitochondrial genome-encoded genes, such as, cytochrome oxidase and NADH dehydrogenase, are up-regulated in diabetic kidneys. A novel nuclear-encoded mitochondrial gene, i.e., translocase inner mitochondrial membrane 44 (Tim44), is up-regulated in diabetic kidneys, and it may also serve as another target for molecular therapeutic intervention at the core storage energy sites, i.e., mitochondria. In this review, these novel differentially regulated genes that respond to hyperglycemic stress are described, and they may serve as possible targets for gene therapy in the treatment of diabetic nephropathy.
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PMID:Gene expression and identification of gene therapy targets in diabetic nephropathy. 1184 17

Several novel genes that are upregulated in diabetic kidneys have been identified. Recently, transforming growth factor beta driven secreted proteins, i.e., connective tissue growth factor and gremlin (bone morphogenetic protein 2), have been identified, and their expression has been correlated with the tissue changes seen in diabetic nephropathy in the adult population. However, there are very few studies reported in the literature that describe the gene expression in the diabetic state during embryonic and neonatal life. It is well known that exposure to glucose or its epimer, i.e., mannose, induces marked dysmorphogenesis of the embryonic metanephros in an organ culture system. These changes are associated with ATP depletion and marked apoptosis, suggesting an oxidant stress in the induction of dysmorphogenesis of the embryonic metanephros. In view of the glucose-induced changes in the fetal metanephros, a diabetic state was induced by the administration of streptozotocin during pregnancy, and newborn mouse kidneys were processed for suppression subtractive hybridization-PCR. In addition, a diabetic state was induced in newborn diabetic mice, and after 1 week their kidneys were harvested and subjected to representational difference analysis of cDNA. Four novel genes with upregulated mRNA expression were identified. They included: (1) a translocase inner mitochondrial membrane 44 that is involved in the ATP-dependent import of preproteins from the cytosol into the mitochondrial matrix; (2) a kidney-specific aldo-keto reductase that utilizes NADPH and NADH as cofactors in the reduction of aromatic aldehydes and aldohexoses; (3) Rap1b, a Ras-related small GTP-binding protein that behaves as a GTPase and cycles between GTP-bound (active) and GDP-bound (inactive) states associated with conformational change, and (4) a fusion protein of ubiquitin polypeptide and ribosomal protein L40 (UbA(52) or ubiquitin/60) that is intimately involved in the ubiquitin-dependent proteasome pathway related to the accelerated degradation of proteins under various stress conditions, such as those seen in patients with cancer and diabetes mellitus.
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PMID:Renal gene expression in embryonic and newborn diabetic mice. 1193 60

The aim of this study was to determine whether aminoguanidine (AG), an inhibitor of advanced glycation, prevents expression of the profibrotic cytokine, connective tissue growth factor (CTGF), as well as accumulation of the previously reported CTGF-dependent matrix protein, fibronectin, in a model of experimental diabetic nephropathy. Diabetic animals were randomly allocated into groups receiving 32 wk of AG or vehicle. Diabetic rats showed increases in CTGF mRNA and protein expression as well as in advanced glycation end-product (AGE) and fibronectin immunostaining, compared with nondiabetic rats. In the diabetic kidney, the increase in CTGF gene and protein expression as well as expression of the extracellular matrix protein fibronectin were prevented by AG. To further explore the relationship between AGEs and mesangial CTGF and fibronectin production, cultured human mesangial cells were exposed in vitro to soluble AGE-BSA and carboxymethyl lysine-BSA, and this led to induction of both CTGF and fibronectin. On the basis of our in vitro findings in mesangial cells linking AGEs to CTGF expression, the known prosclerotic effects of CTGF, and the ability of AG to attenuate mesangial expansion, it is postulated that the antifibrotic effects of AG in this animal model may be partially mediated by CTGF.
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PMID:Renal connective tissue growth factor induction in experimental diabetes is prevented by aminoguanidine. 1244 18

Excessive deposition of fibronectin in the glomerular mesangium in diabetic nephropathy (DN) is partly due to the induction of transforming growth factor-beta (TGF-beta) by high glucose. TGF-beta induces its downstream mediator connective tissue growth factor (CTGF), which stimulates fibronectin matrix synthesis, a process that requires the presence of alpha5beta1 integrin. Although TGF-beta has been shown to upregulate alpha5beta1 integrin expression in human mesangial cells (HMC), little is known about the effect of CTGF on levels of this receptor. This study tested whether CTGF modulates alpha5beta1 expression by HMC in culture and whether changes induced by TGF-beta are mediated through the induction of CTGF. FACS analysis showed that both TGF-beta and CTGF significantly increased cell-surface alpha5beta1 levels compared with basal conditions. RT-PCR indicated that the changes were at the level of transcription. Treatment of cells with TGF-beta and antisense CTGF oligonucleotides significantly reduced the TGF-beta-induced increases in alpha5beta1 levels. CTGF and TGF-beta also significantly increased levels of ligand-occupied cell-surface beta1 integrins and cell adhesion to fibronectin, the main alpha5beta1 substrate. Antisense CTGF significantly reduced the number of adherent cells from TGF-beta-stimulated cultures. Finally, alpha5beta1 blocking antibodies inhibited HMC fibronectin matrix deposition, confirming the importance of this receptor for this process. Taken together, these data provide evidence that CTGF controls alpha5beta1 expression by HMC in vitro. Alterations in alpha5beta1 levels induced by TGF-beta are mediated at least in part through the induction of CTGF, and specific targeting of either alpha5beta1 or CTGF could be useful in controlling excessive fibronectin matrix production in DN.
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PMID:CTGF mediates TGF-beta-induced fibronectin matrix deposition by upregulating active alpha5beta1 integrin in human mesangial cells. 1259 95

Renal accumulation of advanced glycation end products (AGEs) has been linked to the progression of diabetic nephropathy. Cleavage of pre-formed AGEs within the kidney by a cross-link breaker, such as ALT-711, may confer renoprotection in diabetes. STZ diabetic rats were randomized into a) no treatment (D); b) treatment with the AGE cross-link breaker, ALT-711, weeks 16-32 (DALT early); and c) ALT-711, weeks 24-32 (DALT late). Treatment with ALT-711 resulted in a significant reduction in diabetes-induced serum and renal AGE peptide fluorescence, associated with decreases in renal carboxymethyllysine and RAGE immunostaining. Cross-linking of tail tendon collagen seen in diabetic groups was attenuated only by 16 weeks of ALT-711 treatment. ALT-711, independent of treatment duration, retarded albumin excretion rate (AER), reduced blood pressure, and renal hypertrophy. It also reduced diabetes-induced increases in gene expression of transforming growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF), and collagen IV. However, glomerulosclerotic index, tubulointerstitial area, total renal collagen, nitrotyrosine, protein expression of collagen IV, and TGF-beta1 only showed improvement with early ALT treatment alone. This study demonstrates the utility of a cross-link breaker as a treatment for diabetic nephropathy and describes effects not only on renal AGEs but on putative mediators of renal injury, such as prosclerotic cytokines and oxidative stress.
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PMID:The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. 1295 2

The manifestations of diabetic nephropathy may be a consequence of the actions of certain cytokines and growth factors. Prominent among these is transforming growth factor beta (TGF-beta) because it promotes renal cell hypertrophy and stimulates extracellular matrix accumulation, the 2 hallmarks of diabetic renal disease. In tissue culture studies, cellular hypertrophy and matrix production are stimulated by high glucose concentrations in the culture media. High glucose, in turn, appears to act through the TGF-beta system because high glucose increases TGF-beta expression, and the hypertrophic and matrix-stimulatory effects of high glucose are prevented by anti-TGF-beta therapy. In experimental diabetes mellitus, several reports describe overexpression of TGF-beta or TGF-beta type II receptor in the glomerular and tubulointerstitial compartments. As might be expected, the intrarenal TGF-beta system is triggered, evidenced by activity of the downstream Smad signaling pathway. Treatment of diabetic animals with a neutralizing anti-TGF-beta antibody prevents the development of mesangial matrix expansion and the progressive decline in renal function. This antibody therapy also reverses the established lesions of diabetic glomerulopathy. Finally, the renal TGF-beta system is significantly up-regulated in human diabetic nephropathy. Although the kidney of a nondiabetic subject extracts TGF-beta1 from the blood, the kidney of a diabetic patient actually elaborates TGF-beta1 protein into the circulation. Along the same line, an increased level of TGF-beta in the urine is associated with worse clinical outcomes. In concert with TGF-beta, other metabolic mediators such as connective tissue growth factor and reactive oxygen species promote the accumulation of excess matrix. This fibrotic build-up also occurs in the tubulointerstitium, probably as the result of heightened TGF-beta activity that stimulates tubular epithelial and interstitial fibroblast cells to overproduce matrix. The data presented here strongly support the consensus that the TGF-beta system mediates the renal hypertrophy, glomerulosclerosis, and tubulointerstitial fibrosis of diabetic kidney disease.
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PMID:Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up. 1463 61

Tubulointerstitial fibrosis is an important component in the development of diabetic nephropathy. Various renal cell types, including fibroblasts, contribute to the excessive matrix deposition in the kidney. Although transforming growth factor-beta (TGF-beta) has been thought to play a major role during fibrosis, other growth factors are also involved. Here we examined the effects of connective tissue growth factor (CTGF) and IGF-I on collagen type I and III production by human renal fibroblasts and their involvement in glucose-induced matrix accumulation. We have demonstrated that both CTGF and IGF-I expressions were increased in renal fibroblasts under hyperglycemic conditions, also in the absence of TGF-beta signaling. Although CTGF alone had no effect on collagen secretion, combined stimulation with IGF-I enhanced collagen accumulation. Furthermore, IGF-I also had a synergistic effect with glucose on the induction of collagens. Moreover, we observed a partial inhibition in glucose-induced collagen secretion with neutralizing anti-CTGF antibodies, thereby demonstrating for the first time the involvement of endogenous CTGF in glucose-induced effects in human renal fibroblasts. Therefore, the cooperation between CTGF and IGF-I might be involved in glucose-induced matrix accumulation in tubulointerstitial fibrosis and might contribute to the pathogenesis of diabetic nephropathy.
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PMID:Connective tissue growth factor and igf-I are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. 1463 59


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